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Impact of Colchicine on Peri-Operative Major Adverse Cardiovascular Events in Patients With Prior Coronary Revascularization: The Peri-OPerative COlchicine to Reduce Negative Events (POPCORN) Trial (POPCORN)

Primary Purpose

Coronary Artery Disease

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Colchicine
Placebo
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Coronary Artery Disease focused on measuring Coronary artery disease, Non-cardiac surgery, Colchicine, Inflammation, Major adverse cardiovascular events

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Men and women with Prior coronary revascularization (via PCI or coronary artery bypass graft surgery) or high coronary atherosclerotic burden (>70% let main disease or >80% disease in the proximal or mid LAD, prox Cx, or prox or mid RCA on coronary angiography), AND Referred for intermediate- or high-risk surgery (general abdominal or intraperitoneal surgery, neurosurgery, suprainguinal surgery, peripheral vascular surgery, thoracic surgery). If planned for only a laparoscopic or endovascular approach (this includes a minimally invasive hybrid approach such as transcarotid artery revascularization), at least one component of the Revised Cardiac Risk Index score (history of myocardial infarction, history of congestive heart failure, history of transient ischemic attack or stroke, pre-operative use of insulin, pre-operative creatinine >2 mg/dL) should be present. Exclusion Criteria: Colchicine use within one month or history of colchicine intolerance Inflammatory bowel disease with history of diarrhea as presentation or chronic diarrhea Pre-existent progressive neuromuscular disease amyotrophic lateral sclerosis hereditary muscular disorders myositis necrotizing myopathy myasthenia gravis lambert-eaton syndrome Glomerular filtration rate <30mL/minute or on dialysis History of cirrhosis, chronic active hepatitis or severe hepatic disease History of myelodysplasia with current evidence of cytopenia Active infection defined as fever >100.4oF or antibiotic use with white blood cell count greater than the upper limit of normal or lower than the lower limit of normal within 24 hours of randomization (major confounder with increased inflammatory markers) Undergoing immunosuppressive or immunostimulatory chemo or biologic therapy Pregnant (as confirmed by urine or serum test), nursing, or planning to become pregnant during study participation Participating in a competing study or unable to consent Any significant condition or situation that may put the participant at higher risk, confound the study results, or interfere with adherence to study procedures Patients on strong CYP3A4 and/or P-glycoprotein inhibitors (e.g., ritonavir, clarithromycin, diltiazem, verapamil) at baseline will also be excluded due to potential drug interactions However, if one of these medications are started during the post-operative study period, dose adjustments will be made per drug package insert Participants will also be instructed not to drink grapefruit juice while on study drug

Sites / Locations

  • VA Long Beach Healthcare System, Long Beach, CARecruiting
  • Manhattan Campus of the VA NY Harbor Healthcare System, New York, NYRecruiting
  • Durham VA Medical Center, Durham, NC
  • Louis Stokes VA Medical Center, Cleveland, OH
  • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Colchicine

Placebo

Arm Description

One day before surgery: Colchicine 1.2 mg with 0.6 mg PO one hour later. This load will be followed by colchicine 0.6 mg twice daily for a total of 14 days.

Matching placebo at same time points as active comparator

Outcomes

Primary Outcome Measures

Major adverse cardiovascular events
Defined as a composite rate of myocardial injury, non-fatal MI, non-fatal stroke, and all-cause mortality.

Secondary Outcome Measures

rate of myocardial injury
rate of myocardial injury
rate of non-fatal MI
rate of non-fatal MI
rate of non-fatal stroke
rate of non-fatal stroke
rate of all-cause mortality
rate of all-cause mortality
Unplanned coronary revascularization
Unplanned coronary revascularization
Prognostic threshold of myocardial injury
troponin >30 ng/L (high-sensitivity troponin >65 ng/L or absolute change >14 ng/L or 20-65 ng/L with an absolute change of >5 ng/L)
Change in hsCRP
between 1) baseline and one day post-operation, and 2) over time including at two days and 14 days post-operation (or hospital discharge, whichever occurs earlier)

Full Information

First Posted
November 3, 2022
Last Updated
August 2, 2023
Sponsor
VA Office of Research and Development
Collaborators
NYU School of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT05618353
Brief Title
Impact of Colchicine on Peri-Operative Major Adverse Cardiovascular Events in Patients With Prior Coronary Revascularization: The Peri-OPerative COlchicine to Reduce Negative Events (POPCORN) Trial
Acronym
POPCORN
Official Title
Impact of Colchicine on Peri-Operative Major Adverse Cardiovascular Events in Patients With Prior Coronary Revascularization
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 1, 2023 (Actual)
Primary Completion Date
July 31, 2027 (Anticipated)
Study Completion Date
April 30, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development
Collaborators
NYU School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Heart disease remains the leading cause of death in Veterans. Inflammation in the arteries of the heart may increase the risk of cardiac death. Patients with heart disease undergoing major surgery are at increased risk of complications after surgery, including heart attack, stroke, and death. The proposed research seeks to better understand the role of inflammation in the damage to the heart and blood vessels after major surgery. This research also seeks to identify the potential beneficial role of a safe medication, colchicine, which has direct effects on inflammatory cells and has been used in the treatment of inflammatory diseases for more than 2000 years, on reducing the rate of complications after surgery. With its quick onset of action and excellent safety profile, colchicine may have the potential to reduce risk of heart injury, stroke, or death after major surgery.
Detailed Description
Patients with prior coronary revascularization have a high risk of major adverse cardiovascular events (MACE) after major surgery, up to more than 2-fold when compared to patients without prior coronary revascularization. The pro-inflammatory and hypercoagulable states induced by surgery and the hemodynamic changes caused by fluid shifts and anesthesia are all important triggers of perioperative myocardial ischemia. Indeed, peri-operative systemic inflammation is associated with a nearly 4-fold increase in the risk of perioperative MACE. Neutrophils, the most abundant of inflammatory cells, adhere to inflamed or injured endothelium, migrate into the vessel wall, release proteolytic enzymes that can lead to erosion or rupture of plaque. Peri-operative cytokine generation may also activate the inflammasome and, thereby, macrophage-mediated synthesis of interleukin (IL)-1 , a known target for therapy for secondary prevention of MACE, particularly in the setting of high C-reactive protein (CRP) concentration. Colchicine is a safe, well-tolerated anti-inflammatory agent that preferentially accumulates in neutrophils compared with other inflammatory cells. Colchicine inhibits chemotaxis, endothelial adhesion, and extravasation of neutrophils at sites of endothelial injury or inflammation; suppresses the inflammasome-mediated production of IL-1 by macrophages; and reduces inflammation and MACE in patients with cardiovascular disease. The Colchicine Cardiovascular Outcomes Trial and Low Dose Colchicine 2 Trial demonstrated a reduction in MACE with colchicine in about 4000 patients with prior myocardial infarction and about 5000 patients with stable coronary artery disease, respectively. The Colchicine-PCI trial demonstrated for the first time that administration of colchicine prior to injury dampens the inflammatory response measured by CRP. The effects of colchicine on peri-operative MACE in patients with prior coronary revascularization undergoing major surgery, remains unknown. The aims of this trial are to 1) assess the effect of colchicine compared to placebo on peri-operative MACE in response to intermediate- or high-risk non-cardiac surgery in patients with prior coronary revascularization; 2) characterize the level of systemic inflammation and profile of peri-operative neutrophils in this population; and 3) determine the clinical and genetic predictors of peri-operative MACE and examine factors that determine heterogeneity of treatment response in this population. This prospective, double-blinded, placebo-controlled, randomized trial will enroll 700 participants with prior coronary revascularization who undergo intermediate- or high-risk non-cardiac surgery across five VA medical centers that serve as cardiovascular referral centers for their VISNs. Following referral for surgery, and confirmation that the patient meets all study entry criteria, participants will be consented and randomized 1:1 within center to a loading dose of colchicine or placebo one day before surgery and twice daily dosing for 14 days post-operation. DNA will be collected at baseline, while measures of systemic inflammation will be collected at baseline, one day, two days, and at 14 days post-operation (or hospital discharge, whichever occurs earlier). Follow-up for all randomized participants who undergo surgery will occur at 30 days + 7 days.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Coronary Artery Disease
Keywords
Coronary artery disease, Non-cardiac surgery, Colchicine, Inflammation, Major adverse cardiovascular events

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
One day before surgery: Colchicine 1.2 mg with 0.6 mg PO one hour later. This load will be followed by colchicine 0.6 mg twice daily for a total of 14 days. If a patient is unable to take oral medications (by mouth or nasogastric tube) post-operatively (e.g., post abdominal surgery), colchicine will be held until the clinically treating physician allows resumption of oral medications if still within 14 days post-operation.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Matching placebo at the same time points as the intervention
Allocation
Randomized
Enrollment
700 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Colchicine
Arm Type
Active Comparator
Arm Description
One day before surgery: Colchicine 1.2 mg with 0.6 mg PO one hour later. This load will be followed by colchicine 0.6 mg twice daily for a total of 14 days.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo at same time points as active comparator
Intervention Type
Drug
Intervention Name(s)
Colchicine
Other Intervention Name(s)
Colcrys
Intervention Description
0.6 mg tablets
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matching placebo
Primary Outcome Measure Information:
Title
Major adverse cardiovascular events
Description
Defined as a composite rate of myocardial injury, non-fatal MI, non-fatal stroke, and all-cause mortality.
Time Frame
30 days post-operation
Secondary Outcome Measure Information:
Title
rate of myocardial injury
Description
rate of myocardial injury
Time Frame
30 days post-operation
Title
rate of non-fatal MI
Description
rate of non-fatal MI
Time Frame
30 days post-operation
Title
rate of non-fatal stroke
Description
rate of non-fatal stroke
Time Frame
30 days post-operation
Title
rate of all-cause mortality
Description
rate of all-cause mortality
Time Frame
30 days post-operation
Title
Unplanned coronary revascularization
Description
Unplanned coronary revascularization
Time Frame
30 days post-operation
Title
Prognostic threshold of myocardial injury
Description
troponin >30 ng/L (high-sensitivity troponin >65 ng/L or absolute change >14 ng/L or 20-65 ng/L with an absolute change of >5 ng/L)
Time Frame
30 days post-operation
Title
Change in hsCRP
Description
between 1) baseline and one day post-operation, and 2) over time including at two days and 14 days post-operation (or hospital discharge, whichever occurs earlier)
Time Frame
through 14 days post-operation or at hospital discharge, whichever occurs earlier

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men and women with Prior coronary revascularization (via PCI or coronary artery bypass graft surgery) or high coronary atherosclerotic burden (>70% let main disease or >80% disease in the proximal or mid LAD, prox Cx, or prox or mid RCA on coronary angiography), AND Referred for intermediate- or high-risk surgery (general abdominal or intraperitoneal surgery, neurosurgery, suprainguinal surgery, peripheral vascular surgery, thoracic surgery). If planned for only a laparoscopic or endovascular approach (this includes a minimally invasive hybrid approach such as transcarotid artery revascularization), at least one component of the Revised Cardiac Risk Index score (history of myocardial infarction, history of congestive heart failure, history of transient ischemic attack or stroke, pre-operative use of insulin, pre-operative creatinine >2 mg/dL) should be present. Exclusion Criteria: Colchicine use within one month or history of colchicine intolerance Inflammatory bowel disease with history of diarrhea as presentation or chronic diarrhea Pre-existent progressive neuromuscular disease amyotrophic lateral sclerosis hereditary muscular disorders myositis necrotizing myopathy myasthenia gravis lambert-eaton syndrome Glomerular filtration rate <30mL/minute or on dialysis History of cirrhosis, chronic active hepatitis or severe hepatic disease History of myelodysplasia with current evidence of cytopenia Active infection defined as fever >100.4oF or antibiotic use with white blood cell count greater than the upper limit of normal or lower than the lower limit of normal within 24 hours of randomization (major confounder with increased inflammatory markers) Undergoing immunosuppressive or immunostimulatory chemo or biologic therapy Pregnant (as confirmed by urine or serum test), nursing, or planning to become pregnant during study participation Participating in a competing study or unable to consent Any significant condition or situation that may put the participant at higher risk, confound the study results, or interfere with adherence to study procedures Patients on strong CYP3A4 and/or P-glycoprotein inhibitors (e.g., ritonavir, clarithromycin, diltiazem, verapamil) at baseline will also be excluded due to potential drug interactions However, if one of these medications are started during the post-operative study period, dose adjustments will be made per drug package insert Participants will also be instructed not to drink grapefruit juice while on study drug
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Yelena Linchevskaya
Phone
(212) 686-7500
Email
yelena.linchevskaya@va.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Leandro Maranan
Phone
(212) 686-7500
Ext
3926
Email
leandro.maranan@va.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Binita Shah, MD
Organizational Affiliation
Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
Official's Role
Principal Investigator
Facility Information:
Facility Name
VA Long Beach Healthcare System, Long Beach, CA
City
Long Beach
State/Province
California
ZIP/Postal Code
90822
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Najeeb Shirwany
Phone
909-581-2184
Email
najeeb.shirwany@va.gov
First Name & Middle Initial & Last Name & Degree
Arnold Seto
Phone
5628268000
Ext
12876
Email
arnold.seto@va.gov
Facility Name
Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
City
New York
State/Province
New York
ZIP/Postal Code
10010-5011
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
John G Hay, MD
Phone
212-686-7500
Ext
7470
Email
john.hay@va.gov
First Name & Middle Initial & Last Name & Degree
Tricia C Daley-Bowles, PhD
Phone
(212) 686-7500
Ext
4209
Email
tricia.daley-bowles@va.gov
First Name & Middle Initial & Last Name & Degree
Binita Shah, MD
Facility Name
Durham VA Medical Center, Durham, NC
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Julienne Reynolds
Phone
919-286-0411
Email
julienne.reynolds@va.gov
First Name & Middle Initial & Last Name & Degree
Alyssa King
Phone
9192860411
Ext
175222
Email
alyssa.king@va.gov
Facility Name
Louis Stokes VA Medical Center, Cleveland, OH
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Margaret Tiktin
Phone
216-791-3800
Email
margaret.tiktin@va.gov
First Name & Middle Initial & Last Name & Degree
Lauren Huntington
Phone
2167913800
Email
lauren.huntington@va.gov
Facility Name
VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
City
Dallas
State/Province
Texas
ZIP/Postal Code
75216
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kathryn Anderson
Phone
214-857-1808
Email
kathryn.anderson1@va.gov
First Name & Middle Initial & Last Name & Degree
Jennifer McClure
Phone
2148570269
Email
jennifer.mcclure@va.gov

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Impact of Colchicine on Peri-Operative Major Adverse Cardiovascular Events in Patients With Prior Coronary Revascularization: The Peri-OPerative COlchicine to Reduce Negative Events (POPCORN) Trial

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