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| ID | Type | Description | Link |
|---|---|---|---|
| R01HL120905 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Methotrexate | Experimental | Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily |
|
| Colchicine | Experimental | Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily |
|
| Methotrexate & Colchicine | Experimental | Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily |
|
| Placebo | Experimental | Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methotrexate | Drug | Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | At 8 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | At 24 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Robert G Weiss, MD | Johns Hopkins University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Johns Hopkins Hospital | Baltimore | Maryland | 21287 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23895801 | Background | 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. | |
| 23265346 | Background | 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. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Error | Percent change from rest measurement | At 8 weeks |
|
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).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hospitalization | Cardiac disorders | Systematic Assessment | Hospitalization for unstable angina/chest pain |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infection | Infections and infestations | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Robert G. Weiss, MD | Johns Hopkins Hospital | 410-955-1703 | rweiss@jhmi.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 28, 2017 | Sep 1, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003324 | Coronary Artery Disease |
| ID | Term |
|---|---|
| D003327 | Coronary Disease |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D008727 | Methotrexate |
| D003078 | Colchicine |
| ID | Term |
|---|---|
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
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|
| Colchicine | Drug | Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. |
|
|
| Placebo | Drug | Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine. |
|
|
| 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. |
| At 8 weeks |
| 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. | At 8 weeks |
| Serum Interleukin-6 (IL-6) | Serum interleukin-6 (IL-6), measured by laboratory assessment in pg/ml at 8 weeks. | At 8 weeks |
| Brachial Flow Mediated Dilation (FMD) | Brachial flow mediated dilation (FMD), measured as percent brachial artery dilation by ultrasound at 8 weeks. | At 8 weeks |
| 21050976 | Background | 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. |
| 23536782 | Background | Hays AG, Stuber M, Hirsch GA, Yu J, Schar 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. |
| 22492483 | Background | Hays AG, Kelle S, Hirsch GA, Soleimanifard S, Yu J, Agarwal HK, Gerstenblith G, Schar 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. |
| 2233948 | Background | 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. doi: 10.1056/NEJM199012063232304. |
| 34722661 | Derived | Hays AG, Schar M, Bonanno G, Lai S, Meyer J, Afework Y, Steinberg A, Stradley S, Gerstenblith G, Weiss RG. Randomized Trial of Anti-inflammatory Medications and Coronary Endothelial Dysfunction in Patients With Stable Coronary Disease. Front Cardiovasc Med. 2021 Oct 15;8:728654. doi: 10.3389/fcvm.2021.728654. eCollection 2021. |
| BG001 | 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. |
| BG002 | 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. |
| BG003 | 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. |
| BG004 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| 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. |
| OG002 | 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. |
| OG003 | 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. |
|
|
| 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. | 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. | Posted | Mean | Standard Error | Percent change from rest measurement | At 24 weeks |
|
|
|
| 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. | Posted | Mean | Standard Error | Percent change from rest measurement | At 8 weeks |
|
|
|
| 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. | Posted | Mean | Standard Error | mg/l | At 8 weeks |
|
|
|
| Secondary | Serum Interleukin-6 (IL-6) | Serum interleukin-6 (IL-6), measured by laboratory assessment in pg/ml at 8 weeks. | Posted | Mean | Standard Error | pg/ml | At 8 weeks |
|
|
|
| Secondary | Brachial Flow Mediated Dilation (FMD) | Brachial flow mediated dilation (FMD), measured as percent brachial artery dilation by ultrasound at 8 weeks. | Posted | Mean | Standard Error | percent brachial artery dilation | At 8 weeks |
|
|
|
| 0 |
| 24 |
| 3 |
| 24 |
| 22 |
| 24 |
| EG001 | 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. | 0 | 23 | 2 | 23 | 21 | 23 |
| EG002 | 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. | 0 | 24 | 0 | 24 | 23 | 24 |
| EG003 | 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. | 0 | 23 | 1 | 23 | 23 | 23 |
|
| Hospitalization | Musculoskeletal and connective tissue disorders | Systematic Assessment | Hospitalization for shoulder pain |
|
| Hopsitalization | Eye disorders | Systematic Assessment | Hospitalization for transient bilateral vision loss. |
|
| Hospitalization | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Hospitalization for pulmonary symptoms |
|
| Gastrointestinal disorder | Gastrointestinal disorders | Systematic Assessment |
|
| Joint/Muscle Soreness/Stiffness | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Chest Pain | Cardiac disorders | Systematic Assessment |
|
| Extremity swelling | Blood and lymphatic system disorders | Systematic Assessment |
|
| Dental pain/infection | Infections and infestations | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Palpitations | Cardiac disorders | Systematic Assessment |
|
| Physical Injury | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Anxiety/Depression | Psychiatric disorders | Systematic Assessment |
|
| Increased Alanine Amino Trans | Hepatobiliary disorders | Systematic Assessment |
|
| Decreased White Blood Cell | Blood and lymphatic system disorders | Systematic Assessment |
|
| Decreased Hematocrit | Blood and lymphatic system disorders | Systematic Assessment |
|
| Decreased Estimated GFR | Renal and urinary disorders | Systematic Assessment |
|
| Increased Aspartate Amino Trans >3 x the normal range | Hepatobiliary disorders | Systematic Assessment |
|
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| D001161 |
| Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D000072471 |
| Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D000470 | Alkaloids |