COlchicine Improve EnDothElial Function in Non ST Elevation Myocardial Infarction Patients (CODEN)

Does COlchicine Improve EnDothElial Function in Non ST Elevation Myocardial Infarction Patients?: A Prospective Randomized, Double-blind Placebo Controlled Study

Colchicine has antiinflammatory properties. It has been shown to be effective in improving outcome in stable coronary disease. The exact mechanism is unclear. Study objective: to assess the effect of colchicine on endothelial function using the EndoPAT™ in NSTEMI Patients.

Study Hypothesis: There will be a significant difference on the RH-PAT levels of the patients who were in treated with colchicine versus the placebo group Study design and patient Selection One hundred and forty patients with the diagnosis of Non ST Elevation Myocardial Infarction will be enrolled to a prospective randomized double-blind placebo controlled study in Tel Aviv Medical Center, Tel Aviv, Israel. Patients will be recruited during their hospitalization before cardiac catheterization. All patients will sign an informed consent.

Primary outcome will be the improvement in endothelial function between baseline and after 1 month in both groups

Study Overview

• Status: Withdrawn
• Conditions: NSTEMI
• Intervention / Treatment: Drug: Placebo; Drug: Colchicine

Detailed Description

Study design and patient Selection One hundred and forty patients with the diagnosis of Non ST Elevation Myocardial Infarction (NSTEMI) will be enrolled to a prospective randomized double-blind placebo controlled study in Tel Aviv Medical Center, Tel Aviv, Israel. Patients will be recruited during their hospitalization before cardiac catheterization. All patients will sign an inform consent. Study will be published on NIH clinicaltrials.com database.

Inclusion and exclusion criteria are presented in Table 1 Table 1: Patient Selection Inclusion criteria

1. NSTEMI Diagnosis 2. Patients above the age of 18 3. Informed consent Exclusion criteria

1. Hemodynamic instability
2. Pregnant women
3. Peripheral vascular disease with feeble or absent peripheral pulses
4. Restlessness and/or chaotic breathing
5. Renal dialysis
6. Severe aortic valve insufficiency/Stenosis
7. Severe mitral valve insufficiency
8. Congenital cardiac malformations (structural heart diseases)
9. Known extra-cardiac shunts
10. Major surgery within 30 days
11. Any medical condition that would impair participation (e.g. progressive neurological disorders, mental illness)
12. Known intolerance to colchicine
13. Ejection fraction less than 35% or past admission for CHF exacerbation in the last 30 days.
14. Inflammatory diseases
15. Current treatment with steroids, NSAID, chemotherapy or biologic medications

Pre Study exam

After enrollment, patients will undergo the following baseline procedure:

1. Physical examination and medical interview
2. Endothelial function using the EndoPat® before planned cardiac catheterization
3. Blood tests- see below for description

Blood sampling An 18-gauge cannula will be placed in an antecubital vein for blood sampling. Blood sample analyses will be performed using reagents, calibrators and control materials from Bayer Diagnostics (Berkshire, England) on the ADVIA 1650. A 40 ml blood sample will be obtained as described below. Blood tests timing is detailed at the end in the flow chart.

Each Patient will provide 40ml of blood for the following blood tests

1. Full chemistry including: lipid levels, thyroid function, liver enzymes function, Troponin, CPK, HbA1c, uric acid, and glucose levels.
2. Blood count
3. Inflammatory biomarker (hs-CRP, fibrinogen, IL-6, IL-1B, IL-18, MMP, Lp-PLA2, procalcitonin, IL-10, IL-35, TNFa, AchE, , PAI-1, MPO, cholinergic status. etc.)
4. Endothelial function markers: Endothelin-1, I-CAM, V-CAM, superoxide dismutase ADMA, and oxidized LDL
5. Serum Samples will be stored for future testing.

PAT score:

Peripheral arterial tonometry signals will be obtained using the EndoPAT 2000 device (Itamar Medical Inc., Caesarea, Israel), which has been validated and used previously to assess peripheral arterial tone in other populations. 14-17 Briefly, EndoPAT bio-sensors are placed on the index fingers of both arms. EndoPAT quantifies the endothelium-mediated changes in vascular tone, elicited by a 5-minute occlusion of the brachial artery (using a standard blood pressure cuff). When the cuff is released, the surge of blood flow causes an endothelium-dependent Flow Mediated Dilatation (FMD). The dilatation, manifested as reactive hyperemia, is captured by EndoPAT as an increase in the PAT Signal amplitude. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT software, providing the EndoPAT index. In addition, the EndoPAT system will measure heart rate variability.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Israel
  • Tel Aviv, Israel, 64329
    • Tel Aviv Medical Center
  • Tel-Aviv, Israel
    • Sourasky medical center (Ichilov)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. NSTEMI Diagnosis
2. Patients above the age of 18
3. Informed consent

Exclusion Criteria:

1. Hemodynamic instability
2. Pregnant women
3. Peripheral vascular disease with feeble or absent peripheral pulses
4. Restlessness and/or chaotic breathing
5. Renal dialysis
6. Severe aortic valve insufficiency/Stenosis
7. Severe mitral valve insufficiency
8. Congenital cardiac malformations (structural heart diseases)
9. Known extra-cardiac shunts
10. Major surgery within 30 days
11. Any medical condition that would impair participation (e.g. progressive neurological disorders, mental illness)
12. Known intolerance to colchicine
13. Ejection fraction less than 35% or past admission for CHF exacerbation in the last 30 days.
14. Inflammatory diseases
15. Current treatment with steroids, NSAID, chemotherapy or biologic medications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Colchicine; Colchicine 1mg per day for one month	Drug: Colchicine; Colchicine 1mg per day for one month
Placebo Comparator: Placebo; Placebo 1mg per day	Drug: Placebo; Placebo; Other Names: Placebo tablet 1mg per day for a month

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of RH-PAT at 1 month (a marker of endothelial function)	RH-PAT will be measured before the angiography and after one month.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in inflammatory biomarkers (before cardiac catheterization, after cardiac catheterization and at 1 month time follow-up)	biomarkers will be assessed before and after the angiography. Comparison of the biomarker levels will be assessed between the two treatment groups	1 month
Improvement in endothelial function markers.	serum ICAM VACAM and endothelin will be measured	1 month
inflammatory biomarkers Improvement of heart rate variability (HRV)		1 month
Changes in cholinergic status	serum ACHE will be measured at randomization and after one month	1 month
Reduction of Acute Kidney Injury post PCI	AKI will be defined per AKIN as an increase of 0.3mg/dl. The two treatment groups will be compared	1 month
Reduction in radial artery occlusion		acute
Reduction of peri-procedural myocardial infarction		1 month
Major adverse clinical events (MACE) defined as a composite of all-cause mortality, myocardial infarction, repeat revascularization, and 30 day readmission rate		1 month
quality of life under colchicine treatment	The investigators will assess this outcome using a standard quality of life questionnaire (EQ5).	1 month
Safety	Safety will be assessed by comparing adverse events between the two groups	up to 1 year

Collaborators and Investigators

• Sponsor: Tel-Aviv Sourasky Medical Center
• Collaborators: Tel Aviv Medical Center
• Investigators: Principal Investigator: Yaron Arbel, MD, Tel Aviv Medical Center

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: March 6, 2014
• First Submitted That Met QC Criteria: March 20, 2014
• First Posted (Estimate): March 24, 2014

Study Record Updates

• Last Update Posted (Estimate): July 7, 2016
• Last Update Submitted That Met QC Criteria: July 6, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: colchicine NSTEMI endothelial function inflammation
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Non-ST Elevated Myocardial Infarction; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Colchicine
• Other Study ID Numbers: TASMC-13-YA-0636-CTIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO