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Inflammation and Coronary Endothelial Function

Information source: Johns Hopkins University
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Coronary Artery Disease; Elevated C-Reactive Protein

Intervention: Methotrexate (Drug); Colchicine (Drug); Placebo (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Johns Hopkins University

Official(s) and/or principal investigator(s):
Robert G Weiss, MD, Principal Investigator, Affiliation: Johns Hopkins University

Overall contact:
Tricia Steinberg, RN, MSN, Phone: 443-287-3469, Email: asteinb3@jhmi.edu

Summary

The investigators are studying whether anti-inflammatory agents can improve abnormal coronary artery function in patients with coronary artery disease (CAD) and abnormal coronary artery function.

Clinical Details

Official title: Inflammation and Coronary Endothelial Function in Patients With Coronary Artery Disease

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator)

Primary outcome: Coronary segment endothelial function, measured by MRI as the change in coronary cross sectional area (CSA) from rest to that during isometric handgrip exercise (IHE) (as % rest and as mm2).

Secondary outcome:

Change in coronary segment endothelial function, measured by MRI as the change in coronary cross sectional area (CSA) from rest to that during isometric handgrip exercise (IHE) (as % rest and as mm2).

Change in coronary blood velocity (CBV), measured by MRI as the change in CBV from rest to IHE stress (as cm/s and as % rest).

Change in coronary blood flow (CBF), measured by MRI as the change from rest to IHE stress (as cm/s and as % rest).

Serum hs-CRP, measured by laboratory assessment as the change in hs-CRP between baseline and 8 and 24 weeks.

Serum IL-6, measured by laboratory assessment as the change in IL-6 between baseline and 8 and 24 weeks..

Brachial flow mediated dilation (FMD), measured by ultrasound as the change in brachial FMD between baseline and 8 and 24 weeks.

Safety as determined by physical exam and monitoring laboratory values. Measured by assessment for side-effects and laboratory assessment including complete metabolic panel, liver function tests, and complete blood count.

Detailed description: Sometimes, in patients with coronary artery disease (CAD), even though blood pressure is controlled, the patients are on cholesterol medication, not smoking, eating properly and have normal levels of physical activity; the investigators still see development of new blockages, progression of existing blockages, and sometimes even clinical events like heart attacks and strokes. Therefore, the investigators are always trying to find additional ways to decrease the progression of existing blockages and to prevent new ones. What the investigators are studying in this program is the function of the coronary arteries and in particular the inner lining of the arteries called the endothelium. It has several important functions; one of them is that under conditions of stress it releases a substance called nitric oxide which increases the size of the artery and increases blood flow. When it is not functioning normally the artery does not increase as much and blood flow does not increase during stress. The investigators study coronary artery function with magnetic resonance imaging, or MRI. MRI is a method of obtaining images of what is happening inside the body. MRI does not involve radiation, x-ray, and injection of contrast. The investigators can measure flow in the artery and the dimension of the artery at rest and with a handgrip stress and learn the extent to which the artery dilates and flow increases with the stress. The investigators believe that inflammation can interfere with normal function and that by decreasing inflammation abnormal endothelial function may be improved. Methotrexate and colchicine are anti-inflammatory agents approved by the Food and Drug Administration (FDA) to treat arthritis and some other conditions. These drugs are not approved for use to suppress inflammation in patients with coronary artery disease and improve coronary artery endothelial function. The FDA is allowing the use of methotrexate, colchicine and/or their combination in this research study. This study will involve 24 weeks of anti-inflammatory drugs and 3 Magnetic Resonance Imaging (MRI) scans of the heart and other study procedures.

Eligibility

Minimum age: 21 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Participants of either gender who are 21 years of age (no upper age limit),

- History of prior MI, coronary revascularization, or coronary angiography or MDCT

demonstrating at least one coronary artery with ≥50% luminal stenosis and no plans for revascularization,

- Clinically stable for 6 months,

- Evidence of inflammation manifested as elevated hsCRP (>2mg L-1)

- Abnormal CEF (change in CSA during IHE of ≤0% of the resting value: by this we mean

any decrease in CSA or no change (0%) from baseline during IHE),

- Permission of patient's clinical attending physician,

- Patients being treated with a statin.

Exclusion Criteria:

- Patients unable to understand the risks, benefits, and alternatives of participation

and give meaningful consent,

- Patients with contraindications to MRI such as implanted metallic objects

(pre-existing cardiac pacemakers, cerebral clips) or indwelling metallic projectiles,

- Acute coronary syndrome within the prior six months,

- Pregnant women,

- Contraindications to methotrexate or colchicine as outlined by the American College

of Rheumatology; including active bacterial infection, tuberculosis, or herpes zoster infection, leukopenia (<5000/mm3), thrombocytopenia (<150,000/mm3), elevation in hepatic transaminases (>2x upper limit of normal), hepatitis B or C, moderate renal disease (estimated creatine clearance <45ml/min), or planned surgery,

- Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative

colitis or Crohn's disease,

- Interstitial lung disease or pulmonary fibrosis,

- HIV positive,

- Requirement for, or intolerance to, methotrexate, colchicine, or folate,

- History of non-basal cell malignancy or treatment for lymphoproliferative disease in

the past 5 years,

- Requirement for use of drugs that alter folate metabolism,

- History of alcohol abuse or unwillingness to limit consumption to < 4 drinks per

week,

- Women of childbearing potential (even if using oral contraceptive agents) or

intention to breastfeed.

- Men who plan to father children during the study period,

- Chronic use of oral or IV steroid therapy or other immunosuppressive or biologic

response modifiers,

- History of chronic pericardial effusion, pleural effusion or ascites,

- New York Heart Association Class IV heart failure.

Locations and Contacts

Tricia Steinberg, RN, MSN, Phone: 443-287-3469, Email: asteinb3@jhmi.edu

Johns Hopkins Hospital, Baltimore, Maryland 21287, United States; Recruiting
Tricia Steinberg, MSN, Phone: 443-287-3469, Email: asteinb3@jhmi.edu
Additional Information

Related publications:

Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ, Ridker PM. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J. 2013 Aug;166(2):199-207.e15. doi: 10.1016/j.ahj.2013.03.018. Epub 2013 May 3.

Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013 Jan 29;61(4):404-10. doi: 10.1016/j.jacc.2012.10.027. Epub 2012 Dec 19.

Hays AG, Hirsch GA, Kelle S, Gerstenblith G, Weiss RG, Stuber M. Noninvasive visualization of coronary artery endothelial function in healthy subjects and in patients with coronary artery disease. J Am Coll Cardiol. 2010 Nov 9;56(20):1657-65. doi: 10.1016/j.jacc.2010.06.036.

Hays AG, Stuber M, Hirsch GA, Yu J, Schär M, Weiss RG, Gerstenblith G, Kelle S. Non-invasive detection of coronary endothelial response to sequential handgrip exercise in coronary artery disease patients and healthy adults. PLoS One. 2013;8(3):e58047. doi: 10.1371/journal.pone.0058047. Epub 2013 Mar 11.

Hays AG, Kelle S, Hirsch GA, Soleimanifard S, Yu J, Agarwal HK, Gerstenblith G, Schär M, Stuber M, Weiss RG. Regional coronary endothelial function is closely related to local early coronary atherosclerosis in patients with mild coronary artery disease: pilot study. Circ Cardiovasc Imaging. 2012 May 1;5(3):341-8. doi: 10.1161/CIRCIMAGING.111.969691. Epub 2012 Apr 5.

Weiss RG, Bottomley PA, Hardy CJ, Gerstenblith G. Regional myocardial metabolism of high-energy phosphates during isometric exercise in patients with coronary artery disease. N Engl J Med. 1990 Dec 6;323(23):1593-600.

Starting date: January 2015
Last updated: February 11, 2015

Page last updated: August 20, 2015

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