Colchicine for Patients With Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement (Co-STAR)

Colchicine for Patients With Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement (Co-STAR): a Randomized-controlled Trial

Transcatheter aortic valve implantation (TAVI) is a well-established alternative to surgical aortic valve replacement for the treatment of patients with symptomatic severe aortic stenosis. While peri-procedural complications such as stroke, vascular complications and bleeding have substantially declined with the refinement of transcatheter valves and increasing experience, new-onset atrial fibrillation (NOAF) or atrioventricular conduction disturbances continue to occur in almost half of all patients.

Colchicine is a well-known substance that has been approved for the treatment of acute gout flares and familial Mediterranean fever in many countries. Colchicine has proven safe and effective in the prevention of atrial fibrillation after cardiac surgery. The anti-inflammatory effects of colchicine may mitigate the occurrence of atrioventricular conduction disturbances and thus the need for the implantation of a permanent pacemaker post transcatheter aortic valve implantation.

The objective of the Co-STAR-Trial is to investigate the efficacy of colchicine for the prevention of new-onset atrial fibrillation and conduction disturbances requiring the implantation of a permanent pacemaker in patients undergoing transcatheter aortic valve implantation.

Co-STAR is an investigator-initiated, randomized, double blind, placebo-controlled trial. A total of 200 patients referred for treatment of symptomatic severe aortic stenosis and selected to undergo TAVI will be randomized in a 1:1 ratio to the treatment with Colchicine or placebo for 30 days post transcatheter aortic valve implantation.

Study Overview

• Status: Recruiting
• Conditions: Transcatheter Aortic Valve Replacement; Atrial Fibrillation New Onset; Pacemaker; Colchicine
• Intervention / Treatment: Drug: Colchicine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Thomas Pilgrim, Prof.; Phone Number: +41 31 632 08 27; Email: thomas.pilgrim@insel.ch
• Study Contact Backup: Name: Jonas Lanz, Dr. med.; Phone Number: +41 31 632 21 11; Email: jonas.lanz@insel.ch

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Recruiting
    • Inselspital, Bern University Hospital, Department of Cardiology
    • Contact: Thomas Pilgrim, Prof.; Phone Number: +41 31 632 08 27; Email: thomas.pilgrim@insel.ch
    • Contact: Jonas Lanz, Dr. med.; Phone Number: +41 31 632 21 11; Email: jonas.lanz@insel.ch
    • Sub-Investigator: Christoph Ryffel, Dr. med.
    • Sub-Investigator: Jonas Lanz, Dr. med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 65 years
2. Symptomatic severe aortic stenosis defined by an aortic valve area (AVA) ≤1.0 cm2 or an AVA indexed to body surface area <0.6cm2/m2
3. Selected to undergo transfemoral TAVI based on heart team decision

Exclusion Criteria:

1. Life expectancy <1 year irrespective of valvular heart disease
2. Kidney disease with a creatinine clearance ≤30 ml/min
3. Known severe liver disease
4. Known neuromuscular disease
5. Clinically significant anaemia with haemoglobin <80g/L
6. Known inflammatory bowel disease or chronic diarrhea
7. Known ongoing bacterial infection
8. Known galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
9. Current treatment with colchicine, steroids or biologicals for any indication
10. Concomitant intake of Cyclosporine, Amiodarone, Clarithromycin, Erythromycin, Omeprazole, Verapamil or other strong inhibitors of CYP3A4 or P-Glycoprotein
11. Concomitant intake of Carbamazepin, Phenobarbital, Phenytoin, Rifampicin or other strong inductors of CYP3A4 and P-Glycoprotein
12. Permanent pacemaker or implantable cardioverter defibrillator
13. History of atrial fibrillation
14. Absence of sinus rhythm on hospital admission
15. Planned non-cardiac surgery within 30 days
16. Known intolerance to colchicine
17. Inability to provide written informed consent
18. Known or suspected non-compliance, drug or alcohol abuse
19. Participation in another clinical trial with an active intervention
20. Any other planned cardiac intervention performed in the 7 days before TAVI, concomitantly with TAVI or in the 30 days after TAVI except for percutaneous coronary interventions.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo once daily per os the day before TAVI and once at the day of procedure. Thereafter, once daily per os up to post-procedural day 12.
Experimental: Colchicine	Drug: Colchicine; Colchicine in a loading dosage of 1mg single dose per os the day before TAVI and 1mg single dose at the day of procedure. Thereafter, colchicine 0.5mg once daily per os up to post-procedural day 12.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence rate of the composite of new onset atrial fibrillation or occurrence of conduction disturbances requiring the implantation of a permanent pacemaker	Assessed based on extended rhythm monitoring performed until 7 days post-discharge as well as clinically or incidentally captured episodes of NOAF captured during routine care thereafter. NOAF is defined as at least one episode of atrial fibrillation with a duration >30s.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Single components of primary composite endpoint	Including predefine sensitivity analysis using the alternative definition of NOAF: At least one episode of atrial fibrillation with a duration >6 min.	30 days and 1 year
The incidence of conductance disturbances	New or worsened first-degree atrioventricular (AV) block, second-degree AV block (Mobitz I or Mobitz II), high-grade atrioventricular block, third-degree AV block, right bundle branch block, left bundle branch block, left anterior fascicular block, left posterior fascicular block, intraventricular conduction delay	30 days, 1 year
The predictors of conductance disturbances	New or worsened first-degree atrioventricular (AV) block, second-degree AV block (Mobitz I or Mobitz II), high-grade atrioventricular block, third-degree AV block, right bundle branch block, left bundle branch block, left anterior fascicular block, left posterior fascicular block, intraventricular conduction delay	30 days, 1 year
The incidence of new arrhythmias resulting in hemodynamic instability or requiring therapy	Defined as electrical/medical cardioversion or initiation of a new medication e.g. oral anticoagulation, rhythm, or rate controlling therapy	30 days, 1 year
Inflammatory marker levels	IL-6, IL-8, TNF-alpha, IL-1β, CRP, high-sensitivity CRP	at day 1
The proportion of patients with at least one prosthetic leaflet with > 50% motion reduction or with at least one prosthetic leaflet with thickening	Based on a study-specific cardiac computed tomography angiography	30 days
The proportion of prosthetic leaflets with > 50% motion reduction or leaflet thickening	Based on a study-specific cardiac computed tomography angiography	30 days
The incidences of major clinical adverse events	All-cause mortality, stroke, systemic embolism, myocardial infarction, infections, clinical valve thrombosis	30 days, 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Outcome	Incidence of gastrointestinal side effects and clinically severe side effects possibly related to study drug intake	30 days

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Investigators: Principal Investigator: Thomas Pilgrim, Prof., University of Bern, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2021
• Primary Completion (Anticipated): July 31, 2025
• Study Completion (Anticipated): June 30, 2026

Study Registration Dates

• First Submitted: April 22, 2021
• First Submitted That Met QC Criteria: April 28, 2021
• First Posted (Actual): May 3, 2021

Study Record Updates

• Last Update Posted (Actual): January 25, 2023
• Last Update Submitted That Met QC Criteria: January 23, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Atrial Fibrillation; Aortic Valve Stenosis; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Colchicine
• Other Study ID Numbers: Co-STAR

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No