Effects of Interleukin-1 Inhibition on Vascular and Left Ventricular Function in Rheumatoid Arthritis Patients With Coronary Artery Disease
Primary Purpose
Rheumatoid Arthritis, Coronary Artery Disease, Inflammation
Status
Completed
Phase
Not Applicable
Locations
Greece
Study Type
Interventional
Intervention
anakinra
placebo
Sponsored by
About this trial
This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring Arterial stiffness, Endothelial function, Left ventricular function, Apoptosis, Nitrooxidative stress
Eligibility 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
Sites / Locations
- "Attikon" University General Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
anakinra
placebo
Arm Description
Outcomes
Primary Outcome Measures
Improvement in vascular and left ventricular function after anakinra
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01566201
Brief Title
Effects of Interleukin-1 Inhibition on Vascular and Left Ventricular Function in Rheumatoid Arthritis Patients With Coronary Artery Disease
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
Study Type
Interventional
2. Study Status
Record Verification Date
December 2014
Overall Recruitment Status
Completed
Study Start Date
March 2011 (undefined)
Primary Completion Date
April 2012 (Actual)
Study Completion Date
June 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Athens
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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).
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis, Coronary Artery Disease, Inflammation
Keywords
Arterial stiffness, Endothelial function, Left ventricular function, Apoptosis, Nitrooxidative stress
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
80 (Actual)
8. Arms, Groups, and Interventions
Arm Title
anakinra
Arm Type
Active Comparator
Arm Title
placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
anakinra
Other Intervention Name(s)
Kineret® (anakinra)
Intervention Description
Inhibition of Interleukin-1 activity by anakinra (Kineret®) 100mg od, sc injection
Intervention Type
Drug
Intervention Name(s)
placebo
Other Intervention Name(s)
water for injection
Intervention Description
water for injection
Primary Outcome Measure Information:
Title
Improvement in vascular and left ventricular function after anakinra
Description
Improvement in vascular and left ventricular function after administration of anakinra compared to placebo
Time Frame
3 hours after treatment
Secondary Outcome Measure Information:
Title
Reduction of nitrooxidative stress and apoptosis after anakinra treatment
Time Frame
3 hours after treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ignatios Ikonomidis, MD
Organizational Affiliation
2nd Cardiology Department, University of Athens, Greece
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Stavros Tzortzis, MD
Organizational Affiliation
2nd Cardiology Department, University of Athens, Greece
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
John P. Lekakis, MD
Organizational Affiliation
2nd Cardiology Department, University of Athens, Greece
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ioanna Andreadou, Dr
Organizational Affiliation
Department of Pharmaceutical Chemistry, University of Athens Medical School, Greece
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ioannis Paraskevaidis, MD
Organizational Affiliation
2nd Cardiology Department, University of Athens, Greece
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Maria Anastasiou-Nana, MD
Organizational Affiliation
2nd Cardiology Department, University of Athens, Greece
Official's Role
Principal Investigator
Facility Information:
Facility Name
"Attikon" University General Hospital
City
Haidari, Athens
State/Province
Attiki
ZIP/Postal Code
12462
Country
Greece
12. IPD Sharing Statement
Citations:
PubMed Identifier
24782115
Citation
Ikonomidis I, Tzortzis S, Andreadou I, Paraskevaidis I, Katseli C, Katsimbri P, Pavlidis G, Parissis J, Kremastinos D, Anastasiou-Nana M, Lekakis J. Increased benefit of interleukin-1 inhibition on vascular function, myocardial deformation, and twisting in patients with coronary artery disease and coexisting rheumatoid arthritis. Circ Cardiovasc Imaging. 2014 Jul;7(4):619-28. doi: 10.1161/CIRCIMAGING.113.001193. Epub 2014 Apr 29.
Results Reference
derived
Learn more about this trial
Effects of Interleukin-1 Inhibition on Vascular and Left Ventricular Function in Rheumatoid Arthritis Patients With Coronary Artery Disease
We'll reach out to this number within 24 hrs