Inflammation and Coronary Endothelial Function

NCT02366091 | Completed Phase 2 Results DMC

• 2 other identifiers: IRB00047206R01HL120905
• Study Type: interventional
• Target: 111
• Locations: 1 country
• Sites: 1

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.

Conditions

Coronary Artery Disease

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (5)

• Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE)

  At 24 weeks

• Percent Change in Coronary Blood Flow (CBF), Measured by MRI as the Change From Rest to IHE Stress

  At 8 weeks

• Serum High-sensitivity C Reactive Protein (Hs-CRP)

  At 8 weeks

• Serum Interleukin-6 (IL-6)

  At 8 weeks

• Brachial Flow Mediated Dilation (FMD)

  At 8 weeks

Study Arms (4)

Methotrexate

EXPERIMENTAL

Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily

Drug: Methotrexate; Drug: Placebo

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

Drug: Colchicine; Drug: Placebo

Methotrexate & Colchicine

EXPERIMENTAL

Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily

Drug: Methotrexate; Drug: Colchicine

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

Drug: Placebo

Interventions

Methotrexate DRUG

Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease

Also known as: Trexall

Methotrexate; Methotrexate & Colchicine

Colchicine DRUG

Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.

Also known as: Colcrys

Colchicine; Methotrexate & Colchicine

Placebo DRUG

Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.

Also known as: A substance containing no medication

Colchicine; Methotrexate; Placebo

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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,

Sponsors & Collaborators

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

Study Sites (1)

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Related Publications (7)

• 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.

  PMID: 23895801 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.

  PMID: 23265346 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.

  PMID: 21050976 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.

  PMID: 23536782 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.

  PMID: 22492483 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.

  PMID: 2233948 BACKGROUND

• 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.

  PMID: 34722661 DERIVED

MeSH Terms

Conditions

Coronary Artery Disease

Interventions

Methotrexate; Colchicine

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Alkaloids

Results Point of Contact

• Title: Robert G. Weiss, MD
• Organization: Johns Hopkins Hospital

rweiss@jhmi.edu

410-955-1703

Study Officials

• Robert G Weiss, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2015
• First Posted: February 19, 2015
• Study Start: January 1, 2015
• Primary Completion: August 1, 2020
• Study Completion: September 1, 2020
• Last Updated: October 21, 2021
• Results First Posted: October 21, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)