Colchicine in Patients at Cardiac Risk Undergoing Major Non-Cardiac Surgery (COLCAT)

Colchicine in Patients at Cardiac Risk Undergoing Major Non-Cardiac Surgery: Prospective, Randomized, Triple-blinded, Placebo-controlled, Multi-centre Study

Perioperative myocardial injury/infarction (PMI) and major adverse cardiovascular events (MACE) are common causes of morbidity and mortality in patients at increased cardiovascular risk undergoing non-cardiac surgery.

However, research in recent years has yielded limited preventive and therapeutic measures for PMI/MACE. Recent studies in patients with chronic and acute coronary artery disease have shown that colchicine administration can reduce the risk of cardiovascular events.

These encouraging results in non-surgical patients ask for a similar investigation in patients undergoing major non-cardiac surgery. The aim of the proposed study is to investigate the effects of perioperative colchicine administration on the incidence of PMI/MACE.

Study Overview

• Status: Not yet recruiting
• Conditions: Myocardial Infarction; Cardiovascular Diseases; Perioperative Complication; Cardiovascular Complication
• Intervention / Treatment: Drug: Colchicine; Drug: Placebo

Detailed Description

This triple-blind, placebo-controlled study is conducted at the Cantonal Hospital St. Gallen and the University Hospital Basel, Switzerland. The investigators intend to expand the participant recruitment to other centers. Inclusion criteria encompass patients' cardiovascular risk profile and vascular, orthopedic, visceral, and thoracic surgical procedures with a high risk as determined by the recognized incidence of troponin dynamics. Patients are informed during preoperative consultation and provide consent prior to randomization to the colchicine or placebo groups. The preoperative assessment includes medical history, medication use and physical capacity. Baseline values and cardiac biomarkers, are determined through routine laboratory tests. Study medication is administered from the evening before surgery until the third postoperative day. Daily high-sensitivity cardiac troponin T (hs-cTnT) testing is performed until the third day. Visits monitor primary, secondary, and safety endpoints, with standard treatment for complications. Post-hospitalization, cardiovascular events will be recorded until postoperative day 30 and for one year post-surgery to assess long-term outcomes.

The primary objective is to evaluate the efficacy of perioperative colchicine administration in cardiac-risk patients undergoing major non-cardiac surgery, with the aim of reducing the PMI incidence until postoperative day 4 and mitigate postoperative MACE until postoperative day 30. Secondary objectives include whether perioperative administration of colchicine reduces new-onset atrial fibrillation incidence postoperatively (until discharge) compared to placebo, to quantify the maximum increase in postoperative hs-cTnT concentrations until postoperative day 4 and to assess the impact of perioperative colchicine administration on long-term survival and morbidity (composite of MACE) after one year. The safety objectives are the incidence of gastrointestinal adverse events and clinically adverse events attributable to the administration of colchicine.

• Study Type: Interventional
• Enrollment (Estimated): 880
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Timur Yurttas, MD; Phone Number: 0041714949158; Email: timur.yurttas@kssg.ch
• Study Contact Backup: Name: Miodrag Filipovic, Prof. MD.; Phone Number: 0041714941111; Email: miodrag.filipovic@kssg.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

undergoing major non-cardiac surgery in general anaesthesia will be included. Major non-cardiac surgery is defined as:

• vascular surgery (with the exception of arteriovenous shunt, vein stripping procedures and carotid endarterectomies)
• intraperitoneal surgery
• intrathoracic surgery
• major orthopaedic surgery (spinal surgery or joint replacement surgery)

• at cardiovascular risk, defined as meeting at least 1 of the following 6 criteria:

  • preoperative n-terminal pro brain natriuretic peptide (NT-proBNP) ≥ 200 ng/l
  • history of coronary artery disease
  • history of peripheral vascular disease
  • history of stroke
  • undergoing major vascular surgery, with the exception of arteriovenous shunt, vein stripping procedures and carotid endarterectomies

  • fulfilment of any 3 of the 8 following criteria:

    • undergoing major surgery (intrathoracic, intraperitoneal or supra-inguinal vascular surgery)
    • any history of congestive heart failure or history of pulmonary oedema
    • anamnestic transient ischemic attack (TIA)
    • diabetes under treatment with either oral antidiabetic agent or insulin
    • age > 70 years
    • history of hypertension
    • serum creatinine > 175 mumol/l or calculated creatinine clearance < 60 ml/min/1.73m2 (cockcroft gault)
    • history of smoking within 2 years of surgery
    • planned surgical time ≥ 90 minutes
    • planned postoperative hospital stay at least 1 night

Exclusion Criteria:

• no written consent
• inclusion in other clinical trial with direct impact on perioperative medication
• previously reported side effects or reported intolerance from colchicine (e.g., allergic reaction or significant sensitivity to colchicine or an auxiliary substance of the IMP)
• pregnancy or planned pregnancy and/or breast feeding
• clinically significant history of drug or alcohol abuse within the last year
• very severe frailty (≥ 8 clinical frailty scale)
• patient with inflammatory bowel disease (e.g., Morbus Crohn or Colitis ulcerosa)
• patient taking colchicine for other indications (e.g., familial Mediterranean fever, gout)
• severe renal impairment (eGFR < 30 ml min -1 1.73 m2 -1) or end-stage renal disease with indication for haemodialysis
• history of solid organ or bone marrow transplantation
• systemic immune-suppression (medication (steroids >30mg cortisol-equivalent per day, tacrolimus etc...) or disease (e.g., myelodysplastic syndrome)
• severe hepatic impairment with history of cirrhosis
• chronic active hepatitis or functional disorders defined as alanine aminotransferase greater than three times the upper limit of normal
• anticipated post-operative administration of CYP3A4 metabolized substances like cyclosporine, ketoconazole, clarithromycin, verapamil, quinidine, diltiazem or ritonavir
• Any other condition that the investigator would consider a risk to the patient if the latter were to participate in the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Colchicine; The first dose of the IMP is administered in the evening prior to the surgical procedure. Administrations of the study drug follow a 1-0-1 schedule (colchicine 0.5 mg per intake). Thus, half a tablet is taken in the morning and half a tablet in the evening on the day of surgery and so on. The last study drug is administered in the evening of the third postoperative day.	Drug: Colchicine; Colchicine Group: IMP = Colchicine (0.5 mg, enteral) first application in the evening before day of surgery, following a 1-0-1 regimen until the third postoperative day, ending with the application of the ninth dose. Colchicine tablets are provided as 1 mg tablets with a score, which must be divided before ingestion.
Placebo Comparator: Control (Placebo); Patients in the control group will receive the same perioperative anaesthetic, surgical and medical treatment as patients in the experimental group, the sole difference being that patients will be given a placebo instead of the IMP colchicine. The first dose of the placebo is administered in the evening prior to the surgical procedure. Administrations of the placebo follow a 1-0-1 schedule. Thus, half a tablet is also taken in the morning and half a tablet in the evening on the day of surgery and so on. The last placebo is administered in the evening of the third postoperative day.	Drug: Placebo; Placebo Group: Placebo (identical to IMP in appearance and application) first application in the evening before day of surgery, following a 1-0-1 regimen until the third postoperative day, ending with the application of the ninth dose. Placebo tablets are provided as tablets with a score, which must be divided before ingestion.; Other Names: Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perioperative Myocardial Injury/Infarction	Proportion of patients developing PMI in the peri- postoperative course. The primary outcome is a composite of PMI and 30-day MACE. PMI is defined as an absolute perioperative rise in hs-cTnT of ≥ 14 ng/l above preoperative values (or between two postoperative measurements, if preoperative hs-cTnT is missing).	until postoperative day 4
Major Adverse Cardiovascular Events	Proportion of patients developing MACE in the peri- postoperative course. MACE is defined as a composite of any of the following within 30 days following surgery: Acute coronary syndrome; New/worsening congestive heart failure; Coronary revascularization; Stroke; All-cause mortality; Cardiovascular death	until postoperative day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
long term cardiovascular outcome	Proportion of patients developing MACE in regard of long term cardiovascular outcome after surgery.1-year composite endpoint of MACE (composite of acute coronary syndrome, new or worsening congestive heart failure, coronary revascularization, stroke, all-cause mortality and cardiovascular mortality) as a marker of long-term postoperative outcome.	until 1 year after surgery
New onset Atrial fibrillation	Proportion of patients developing new-onset atrial fibrillation in the peri- postoperative course. The time frame includes the time from beginning of surgery (ECG monitoring in the peri- and early postoperative course on postoperative care unit/intensive care unit) until the date of first documented occurrence of atrial fibrillation (perioperative monitoring by daily nurse-controlled pulse examination, verified by an ECG in case of suspected arrhythmia/atrial fibrillation). These monitoring procedures take place until the discharge from the hospital.	From beginning of surgery/surgical procedures until the date of first documented occurrence or until postoperative day 30/discharge from hospital, whatever comes first
postoperative high sensitive cardiac Troponin T concentrations	Comparison of postoperative hs-cTnT concentrations (maximal increase from individual baseline & the area under the curve) until postoperative day 4 between the study groups	until postoperative day 4

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastrointestinal adverse events	Proportion of patients developing gastrointestinal side effects as: diarrhoea, abdominal cramping, abdominal pain, vomiting, nausea after the intervention	From the first intake of the study drug until 72 hours after the last intake of the study drug (i.e., postoperative day 6) or until discharge from the hospital, whatever comes first

Collaborators and Investigators

• Sponsor: Cantonal Hospital of St. Gallen

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2028

Study Registration Dates

• First Submitted: February 12, 2024
• First Submitted That Met QC Criteria: February 23, 2024
• First Posted (Actual): February 26, 2024

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Perioperative Myocardial Infarction/Injury; Perioperative Cardiovascular Risk
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Cardiovascular Diseases; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Colchicine
• Other Study ID Numbers: CTU 22/025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No