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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)

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ClinicalTrials.gov Identifier: NCT05618353
Recruitment Status : Recruiting
First Posted : November 16, 2022
Last Update Posted : August 3, 2023
Sponsor:
Collaborator:
NYU School of Medicine
Information provided by (Responsible Party):
VA Office of Research and Development

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.

Condition or disease Intervention/treatment Phase
Coronary Artery Disease Drug: Colchicine Drug: Placebo Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 700 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Matching placebo at the same time points as the intervention
Primary Purpose: Treatment
Official Title: Impact of Colchicine on Peri-Operative Major Adverse Cardiovascular Events in Patients With Prior Coronary Revascularization
Actual Study Start Date : August 1, 2023
Estimated Primary Completion Date : July 31, 2027
Estimated Study Completion Date : April 30, 2028

Resource links provided by the National Library of Medicine

Drug Information available for: Colchicine

Arm Intervention/treatment
Active Comparator: Colchicine
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.
Drug: Colchicine
0.6 mg tablets
Other Name: Colcrys

Placebo Comparator: Placebo
Matching placebo at same time points as active comparator
Drug: Placebo
Matching placebo




Primary Outcome Measures :
  1. Major adverse cardiovascular events [ Time Frame: 30 days post-operation ]
    Defined as a composite rate of myocardial injury, non-fatal MI, non-fatal stroke, and all-cause mortality.


Secondary Outcome Measures :
  1. rate of myocardial injury [ Time Frame: 30 days post-operation ]
    rate of myocardial injury

  2. rate of non-fatal MI [ Time Frame: 30 days post-operation ]
    rate of non-fatal MI

  3. rate of non-fatal stroke [ Time Frame: 30 days post-operation ]
    rate of non-fatal stroke

  4. rate of all-cause mortality [ Time Frame: 30 days post-operation ]
    rate of all-cause mortality

  5. Unplanned coronary revascularization [ Time Frame: 30 days post-operation ]
    Unplanned coronary revascularization

  6. Prognostic threshold of myocardial injury [ Time Frame: 30 days post-operation ]
    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)

  7. Change in hsCRP [ Time Frame: through 14 days post-operation or at hospital discharge, whichever occurs earlier ]
    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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05618353


Contacts
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Contact: Yelena Linchevskaya (212) 686-7500 yelena.linchevskaya@va.gov
Contact: Leandro Maranan (212) 686-7500 ext 3926 leandro.maranan@va.gov

Locations
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United States, California
VA Long Beach Healthcare System, Long Beach, CA Recruiting
Long Beach, California, United States, 90822
Contact: Najeeb Shirwany    909-581-2184    najeeb.shirwany@va.gov   
Contact: Arnold Seto    5628268000 ext 12876    arnold.seto@va.gov   
United States, New York
Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY Recruiting
New York, New York, United States, 10010-5011
Contact: John G Hay, MD    212-686-7500 ext 7470    john.hay@va.gov   
Contact: Tricia C Daley-Bowles, PhD    (212) 686-7500 ext 4209    tricia.daley-bowles@va.gov   
Principal Investigator: Binita Shah, MD         
United States, North Carolina
Durham VA Medical Center, Durham, NC Not yet recruiting
Durham, North Carolina, United States, 27705
Contact: Julienne Reynolds    919-286-0411    julienne.reynolds@va.gov   
Contact: Alyssa King    9192860411 ext 175222    alyssa.king@va.gov   
United States, Ohio
Louis Stokes VA Medical Center, Cleveland, OH Not yet recruiting
Cleveland, Ohio, United States, 44106
Contact: Margaret Tiktin    216-791-3800    margaret.tiktin@va.gov   
Contact: Lauren Huntington    2167913800    lauren.huntington@va.gov   
United States, Texas
VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX Not yet recruiting
Dallas, Texas, United States, 75216
Contact: Kathryn Anderson    214-857-1808    kathryn.anderson1@va.gov   
Contact: Jennifer McClure    2148570269    jennifer.mcclure@va.gov   
Sponsors and Collaborators
VA Office of Research and Development
NYU School of Medicine
Investigators
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Principal Investigator: Binita Shah, MD Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT05618353    
Other Study ID Numbers: CARA-003-22S
I01CX002358-01A2 ( U.S. NIH Grant/Contract )
First Posted: November 16, 2022    Key Record Dates
Last Update Posted: August 3, 2023
Last Verified: August 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by VA Office of Research and Development:
Coronary artery disease
Non-cardiac surgery
Colchicine
Inflammation
Major adverse cardiovascular events
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Colchicine
Gout Suppressants
Antirheumatic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents