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Inflammation and Coronary Endothelial Function

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ClinicalTrials.gov Identifier: NCT02366091
Recruitment Status : Active, not recruiting
First Posted : February 19, 2015
Last Update Posted : September 12, 2019
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Robert G. Weiss, Johns Hopkins University

Brief 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 endothelial function.

Condition or disease Intervention/treatment Phase
Coronary Artery Disease Drug: Methotrexate Drug: Colchicine Drug: Placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Other
Official Title: Inflammation and Coronary Endothelial Function in Patients With Coronary Artery Disease
Actual Study Start Date : January 2015
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : February 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Methotrexate
Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily
Drug: Methotrexate
Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease
Other Name: Trexall

Drug: Placebo
Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Other Name: A substance containing no medication

Experimental: Colchicine
Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily
Drug: Colchicine
Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.
Other Name: Colcrys

Drug: Placebo
Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Other Name: A substance containing no medication

Experimental: Methotrexate & Colchicine
Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily
Drug: Methotrexate
Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease
Other Name: Trexall

Drug: Colchicine
Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.
Other Name: Colcrys

Experimental: Placebo
Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily
Drug: Placebo
Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Other Name: A substance containing no medication




Primary Outcome Measures :
  1. 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). [ Time Frame: 8 weeks ]

Secondary Outcome Measures :
  1. 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). [ Time Frame: 24 weeks ]
  2. 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). [ Time Frame: 8 and 24 weeks ]
  3. Change in coronary blood flow (CBF), measured by MRI as the change from rest to IHE stress (as cm/s and as % rest). [ Time Frame: 8 and 24 weeks ]
  4. Serum high-sensitivity C reactive protein (hs-CRP), measured by laboratory assessment as the change in hs-CRP between baseline and 8 and 24 weeks. [ Time Frame: 8 and 24 weeks ]
  5. Serum interleukin-6 (IL-6), measured by laboratory assessment as the change in IL-6 between baseline and 8 and 24 weeks.. [ Time Frame: 8 and 24 weeks ]
  6. Brachial flow mediated dilation (FMD), measured by ultrasound as the change in brachial FMD between baseline and 8 and 24 weeks. [ Time Frame: 8 and 24 weeks ]
  7. 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. [ Time Frame: Every 4 weeks through 28 weeks ]


Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants of either gender who are 21 years of age (no upper age limit),
  • History of prior Myocardial Infarction (MI), coronary revascularization, or coronary angiography or Multidetector Computer Tomography (MDCT) demonstrating at least one coronary artery with >50% luminal stenosis and no plans for revascularization,
  • Clinically stable for 3 months,
  • Vascular inflammation based on elevated hsCRP (>2mg L-1), or a clinical diagnosis of diabetes mellitus or metabolic syndrome (metabolic syndrome is defined by three or more of the following): Abdominal obesity (waist circumference: Men>102 cm (>40 in), Women >88 cm (>35 in)), Serum triglycerides ≥150 mg/dL (or taking medication to treat high triglycerides), HDL cholesterol: Men<40 mg/dL, Women<50 mg/dL (or taking medication to treat low HDL cholesterol), High blood pressure: ≥130/≥85 mm Hg (or taking medication to treat high blood pressure), or Fasting glucose: ≥100 mg/dL (or taking medication to treat high fasting glucose).
  • Abnormal Coronary Endothelial Function (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 three 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 (<4000/mm3), thrombocytopenia (<135,000/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 or colchicine ,
  • 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 or intention to breastfeed.
  • Men who plan to father children during the study period; men who have sexual intercourse with women of childbearing potential must agree to use a condom,
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02366091


Locations
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United States, Maryland
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Johns Hopkins University
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Robert G Weiss, MD Johns Hopkins University

Publications:

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Responsible Party: Robert G. Weiss, Professor of Medicine and Radiology, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT02366091     History of Changes
Other Study ID Numbers: IRB00047206
R01HL120905 ( U.S. NIH Grant/Contract )
First Posted: February 19, 2015    Key Record Dates
Last Update Posted: September 12, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Inflammation
Pathologic Processes
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Methotrexate
Colchicine
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Gout Suppressants
Tubulin Modulators
Antimitotic Agents