Inflammation and Coronary Endothelial Function

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02366091
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 111
• Location: 1
• Arms: 4
• Actual Duration (Months): 68
• Patients Per Site Per Month: 1.6

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 111 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: Jan 1, 2015
• Actual Primary Completion Date: Aug 1, 2020
• Actual Study Completion Date: Sep 1, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE) [At 8 weeks]

   Coronary segment endothelial function, measured by MRI as the percent change in coronary cross sectional area (CSA) from rest to that during isometric handgrip exercise (IHE) (as % rest) at 8 weeks.

Secondary Outcome Measures

1. Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE) [At 24 weeks]

   Change in coronary segment endothelial function, measured by MRI as the percent change in coronary cross sectional area (CSA) from rest to that during isometric handgrip exercise (IHE) (as % rest) at 24 weeks.

2. Percent Change in Coronary Blood Flow (CBF), Measured by MRI as the Change From Rest to IHE Stress [At 8 weeks]

   Change in coronary blood flow (CBF), measured by MRI as the percent change from rest to IHE stress (as % rest) at 8 weeks.

3. Serum High-sensitivity C Reactive Protein (Hs-CRP) [At 8 weeks]

   Serum high-sensitivity C reactive protein (hs-CRP), measured by laboratory assessment in mg/l at 8 weeks.

4. Serum Interleukin-6 (IL-6) [At 8 weeks]

   Serum interleukin-6 (IL-6), measured by laboratory assessment in pg/ml at 8 weeks.

5. Brachial Flow Mediated Dilation (FMD) [At 8 weeks]

   Brachial flow mediated dilation (FMD), measured as percent brachial artery dilation by ultrasound at 8 weeks.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Johns Hopkins University
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Robert G Weiss, MD, Johns Hopkins University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 28, 2017

More Information

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.
• 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, 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.
• 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.
• 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):404-410. doi: 10.1016/j.jacc.2012.10.027. Epub 2012 Dec 19.
• 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.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT02366091
• Other Study ID Numbers: IRB00047206; R01HL120905
• First Posted: Feb 19, 2015
• Last Update Posted: Oct 21, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Inflammation; Methotrexate; Colchicine

Study Results

Participant Flow

Pre-assignment Detail	17 enrolled participants were excluded from the study prior to randomization as follows: 9 did not qualify by screening MRI; 3 did not qualify by lab work; 3 declined to proceed after qualifying by MRI; 2 were not randomized as enrollment target was met.

Arm/Group Title	Methotrexate	Colchicine	Methotrexate & Colchicine	Placebo
Arm/Group Description	Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.	Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Period Title: Overall Study
STARTED	24	23	24	23
COMPLETED	21	16	21	22
NOT COMPLETED	3	7	3	1

Baseline Characteristics

Arm/Group Title	Methotrexate	Colchicine	Methotrexate & Colchicine	Placebo	Total
Arm/Group Description	Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.	Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Total of all reporting groups
Overall Participants	24	23	24	23	94
Age (Years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Years]	61.6	66.8	63.4	63.9	63.77
Sex: Female, Male (Count of Participants)
Female	6 25%	2 8.7%	3 12.5%	2 8.7%	13 13.8%
Male	18 75%	21 91.3%	21 87.5%	21 91.3%	81 86.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.2%	1 4.3%	1 4.2%	1 4.3%	4 4.3%
Not Hispanic or Latino	23 95.8%	22 95.7%	23 95.8%	22 95.7%	90 95.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 4.2%	1 4.3%	0 0%	1 4.3%	3 3.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 8.3%	3 13%	2 8.3%	2 8.7%	9 9.6%
White	20 83.3%	19 82.6%	21 87.5%	19 82.6%	79 84%
More than one race	0 0%	0 0%	0 0%	1 4.3%	1 1.1%
Unknown or Not Reported	1 4.2%	0 0%	1 4.2%	0 0%	2 2.1%

Outcome Measures

1. Primary Outcome

Title	Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE)
Description	Coronary segment endothelial function, measured by MRI as the percent change in coronary cross sectional area (CSA) from rest to that during isometric handgrip exercise (IHE) (as % rest) at 8 weeks.
Time Frame	At 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methotrexate	Colchicine	Methotrexate & Colchicine	Placebo
Arm/Group Description	Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.	Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Measure Participants	21	16	21	22
Mean (Standard Error) [Percent change from rest measurement]	-1.70 (2.85)	2.71 (3.74)	-0.39 (2.23)	2.04 (2.05)

2. Secondary Outcome

Title	Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE)
Description	Change in coronary segment endothelial function, measured by MRI as the percent change in coronary cross sectional area (CSA) from rest to that during isometric handgrip exercise (IHE) (as % rest) at 24 weeks.
Time Frame	At 24 weeks

Outcome Measure Data

Analysis Population Description

Not all participants who completed the primary outcome at 8 weeks went on to complete the 24 week studies, resulting in different numbers of participants analyzed between weeks 8 and 24.

Arm/Group Title	Methotrexate	Colchicine	Methotrexate & Colchicine	Placebo
Arm/Group Description	Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.	Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Measure Participants	18	12	17	20
Mean (Standard Error) [Percent change from rest measurement]	1.94 (3.36)	-5.39 (3.91)	2.64 (2.60)	9.26 (2.91)

3. Secondary Outcome

Title	Percent Change in Coronary Blood Flow (CBF), Measured by MRI as the Change From Rest to IHE Stress
Description	Change in coronary blood flow (CBF), measured by MRI as the percent change from rest to IHE stress (as % rest) at 8 weeks.
Time Frame	At 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methotrexate	Colchicine	Methotrexate & Colchicine	Placebo
Arm/Group Description	Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.	Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Measure Participants	21	16	21	22
Mean (Standard Error) [Percent change from rest measurement]	10.23 (4.70)	14.06 (4.57)	12.38 (5.58)	13.81 (4.68)

4. Secondary Outcome

Title	Serum High-sensitivity C Reactive Protein (Hs-CRP)
Description	Serum high-sensitivity C reactive protein (hs-CRP), measured by laboratory assessment in mg/l at 8 weeks.
Time Frame	At 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methotrexate	Colchicine	Methotrexate & Colchicine	Placebo
Arm/Group Description	Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.	Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Measure Participants	21	16	21	22
Mean (Standard Error) [mg/l]	2.40 (0.54)	3.10 (1.68)	1.45 (0.22)	1.65 (0.39)

5. Secondary Outcome

Title	Serum Interleukin-6 (IL-6)
Description	Serum interleukin-6 (IL-6), measured by laboratory assessment in pg/ml at 8 weeks.
Time Frame	At 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methotrexate	Colchicine	Methotrexate & Colchicine	Placebo
Arm/Group Description	Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.	Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Measure Participants	21	16	21	22
Mean (Standard Error) [pg/ml]	1.61 (0.55)	1.20 (0.27)	0.83 (0.07)	0.92 (0.07)

6. Secondary Outcome

Title	Brachial Flow Mediated Dilation (FMD)
Description	Brachial flow mediated dilation (FMD), measured as percent brachial artery dilation by ultrasound at 8 weeks.
Time Frame	At 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methotrexate	Colchicine	Methotrexate & Colchicine	Placebo
Arm/Group Description	Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.	Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.	Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Measure Participants	21	16	21	22
Mean (Standard Error) [percent brachial artery dilation]	4.37 (0.70)	3.23 (0.52)	3.58 (0.48)	4.57 (0.60)

Adverse Events

Time Frame	Adverse event data were collected over study enrollment and up to 4 weeks after the last dose of the study drug (total up to 28 weeks after initiation of study drug).
Arm/Group Title	Methotrexate		Colchicine		Methotrexate & Colchicine		Placebo
Arm/Group Description	Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.		Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.		Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily Methotrexate: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.		Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
All Cause Mortality
	Methotrexate		Colchicine		Methotrexate & Colchicine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/23 (0%)		0/24 (0%)		0/23 (0%)
Serious Adverse Events
	Methotrexate		Colchicine		Methotrexate & Colchicine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/24 (12.5%)		2/23 (8.7%)		0/24 (0%)		1/23 (4.3%)
Cardiac disorders
Hospitalization	0/24 (0%)	0	1/23 (4.3%)	1	0/24 (0%)	0	1/23 (4.3%)	1
Eye disorders
Hopsitalization	1/24 (4.2%)	1	0/23 (0%)	0	0/24 (0%)	0	0/23 (0%)	0
Musculoskeletal and connective tissue disorders
Hospitalization	2/24 (8.3%)	2	0/23 (0%)	0	0/24 (0%)	0	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hospitalization	0/24 (0%)	0	1/23 (4.3%)	1	0/24 (0%)	0	0/23 (0%)	0
Other (Not Including Serious) Adverse Events
	Methotrexate		Colchicine		Methotrexate & Colchicine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/24 (91.7%)		21/23 (91.3%)		23/24 (95.8%)		23/23 (100%)
Blood and lymphatic system disorders
Extremity swelling	1/24 (4.2%)	1	2/23 (8.7%)	2	0/24 (0%)	0	1/23 (4.3%)	1
Decreased White Blood Cell	1/24 (4.2%)	1	2/23 (8.7%)	2	1/24 (4.2%)	1	3/23 (13%)	3
Decreased Hematocrit	4/24 (16.7%)	4	6/23 (26.1%)	6	8/24 (33.3%)	8	6/23 (26.1%)	6
Cardiac disorders
Chest Pain	1/24 (4.2%)	1	1/23 (4.3%)	1	1/24 (4.2%)	1	1/23 (4.3%)	1
Palpitations	1/24 (4.2%)	1	1/23 (4.3%)	1	1/24 (4.2%)	1	0/23 (0%)	0
Gastrointestinal disorders
Gastrointestinal disorder	9/24 (37.5%)	9	9/23 (39.1%)	9	7/24 (29.2%)	7	2/23 (8.7%)	2
Hepatobiliary disorders
Increased Alanine Amino Trans	0/24 (0%)	0	0/23 (0%)	0	1/24 (4.2%)	1	0/23 (0%)	0
Increased Aspartate Amino Trans >3 x the normal range	0/24 (0%)	0	0/23 (0%)	0	1/24 (4.2%)	1	0/23 (0%)	0
Infections and infestations
Infection	8/24 (33.3%)	8	8/23 (34.8%)	8	9/24 (37.5%)	9	6/23 (26.1%)	6
Dental pain/infection	0/24 (0%)	0	1/23 (4.3%)	1	2/24 (8.3%)	2	1/23 (4.3%)	1
Injury, poisoning and procedural complications
Physical Injury	4/24 (16.7%)	4	2/23 (8.7%)	2	1/24 (4.2%)	1	2/23 (8.7%)	2
Musculoskeletal and connective tissue disorders
Joint/Muscle Soreness/Stiffness	5/24 (20.8%)	5	2/23 (8.7%)	2	7/24 (29.2%)	7	7/23 (30.4%)	7
Psychiatric disorders
Anxiety/Depression	0/24 (0%)	0	1/23 (4.3%)	1	3/24 (12.5%)	3	0/23 (0%)	0
Renal and urinary disorders
Decreased Estimated GFR	5/24 (20.8%)	5	1/23 (4.3%)	1	3/24 (12.5%)	3	4/23 (17.4%)	4
Skin and subcutaneous tissue disorders
Rash	2/24 (8.3%)	2	2/23 (8.7%)	2	1/24 (4.2%)	1	0/23 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.