Coronary Artery Disease
Conditions
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.
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.
Interventions
DRUGMethotrexate
Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease
DRUGColchicine
Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.
DRUGPlacebo
Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| Serum Interleukin-6 (IL-6) | At 8 weeks | Serum interleukin-6 (IL-6), measured by laboratory assessment in pg/ml at 8 weeks. |
| Brachial Flow Mediated Dilation (FMD) | At 8 weeks | Brachial flow mediated dilation (FMD), measured as percent brachial artery dilation by ultrasound at 8 weeks. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Methotrexate 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. | 24 |
| 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. | 23 |
| Methotrexate & 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. | 24 |
| 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
Placebo: Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine. | 23 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 7 | 3 | 1 |
Baseline characteristics
| Characteristic | Methotrexate | Colchicine | Methotrexate & Colchicine | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 61.6 Years | 66.8 Years | 63.4 Years | 63.9 Years | 63.77 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 22 Participants | 23 Participants | 22 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 20 Participants | 19 Participants | 21 Participants | 19 Participants | 79 Participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 3 Participants | 2 Participants | 13 Participants |
| Sex: Female, Male Male | 18 Participants | 21 Participants | 21 Participants | 21 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 23 | 0 / 24 | 0 / 23 |
| other Total, other adverse events | 22 / 24 | 21 / 23 | 23 / 24 | 23 / 23 |
| serious Total, serious adverse events | 3 / 24 | 2 / 23 | 0 / 24 | 1 / 23 |
Outcome results
Primary
Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE)
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE) | -1.70 Percent change from rest measurement | Standard Error 2.85 |
| Colchicine | Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE) | 2.71 Percent change from rest measurement | Standard Error 3.74 |
| Methotrexate & Colchicine | Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE) | -0.39 Percent change from rest measurement | Standard Error 2.23 |
| Placebo | Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE) | 2.04 Percent change from rest measurement | Standard Error 2.05 |
Secondary
Brachial Flow Mediated Dilation (FMD)
Brachial flow mediated dilation (FMD), measured as percent brachial artery dilation by ultrasound at 8 weeks.
Time frame: At 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Brachial Flow Mediated Dilation (FMD) | 4.37 percent brachial artery dilation | Standard Error 0.7 |
| Colchicine | Brachial Flow Mediated Dilation (FMD) | 3.23 percent brachial artery dilation | Standard Error 0.52 |
| Methotrexate & Colchicine | Brachial Flow Mediated Dilation (FMD) | 3.58 percent brachial artery dilation | Standard Error 0.48 |
| Placebo | Brachial Flow Mediated Dilation (FMD) | 4.57 percent brachial artery dilation | Standard Error 0.6 |
Secondary
Percent Change in Coronary Blood Flow (CBF), Measured by MRI as the Change From Rest to IHE Stress
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Percent Change in Coronary Blood Flow (CBF), Measured by MRI as the Change From Rest to IHE Stress | 10.23 Percent change from rest measurement | Standard Error 4.7 |
| Colchicine | Percent Change in Coronary Blood Flow (CBF), Measured by MRI as the Change From Rest to IHE Stress | 14.06 Percent change from rest measurement | Standard Error 4.57 |
| Methotrexate & Colchicine | Percent Change in Coronary Blood Flow (CBF), Measured by MRI as the Change From Rest to IHE Stress | 12.38 Percent change from rest measurement | Standard Error 5.58 |
| Placebo | Percent Change in Coronary Blood Flow (CBF), Measured by MRI as the Change From Rest to IHE Stress | 13.81 Percent change from rest measurement | Standard Error 4.68 |
Secondary
Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE) | 1.94 Percent change from rest measurement | Standard Error 3.36 |
| Colchicine | Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE) | -5.39 Percent change from rest measurement | Standard Error 3.91 |
| Methotrexate & Colchicine | Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE) | 2.64 Percent change from rest measurement | Standard Error 2.6 |
| Placebo | Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE) | 9.26 Percent change from rest measurement | Standard Error 2.91 |
Secondary
Serum High-sensitivity C Reactive Protein (Hs-CRP)
Serum high-sensitivity C reactive protein (hs-CRP), measured by laboratory assessment in mg/l at 8 weeks.
Time frame: At 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Serum High-sensitivity C Reactive Protein (Hs-CRP) | 2.40 mg/l | Standard Error 0.54 |
| Colchicine | Serum High-sensitivity C Reactive Protein (Hs-CRP) | 3.10 mg/l | Standard Error 1.68 |
| Methotrexate & Colchicine | Serum High-sensitivity C Reactive Protein (Hs-CRP) | 1.45 mg/l | Standard Error 0.22 |
| Placebo | Serum High-sensitivity C Reactive Protein (Hs-CRP) | 1.65 mg/l | Standard Error 0.39 |
Secondary
Serum Interleukin-6 (IL-6)
Serum interleukin-6 (IL-6), measured by laboratory assessment in pg/ml at 8 weeks.
Time frame: At 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Serum Interleukin-6 (IL-6) | 1.61 pg/ml | Standard Error 0.55 |
| Colchicine | Serum Interleukin-6 (IL-6) | 1.20 pg/ml | Standard Error 0.27 |
| Methotrexate & Colchicine | Serum Interleukin-6 (IL-6) | 0.83 pg/ml | Standard Error 0.07 |
| Placebo | Serum Interleukin-6 (IL-6) | 0.92 pg/ml | Standard Error 0.07 |