Clinical trial NCT05855746: Colchicine Versus Placebo in Acute Myocarditis Patients
Official title: Colchicine Versus Placebo in Acute Myocarditis Patients to Reduce Late Gadolinium Enhancement Mass on Cardiac Magnetic Resonance and the Risk of Clinical Outcomes: The ARGO Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Myocarditis
Keywords: Myocarditis
Inflammation
Colchicine
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Hospices Civils de Lyon
name: Fonds de Dotation ACTION
First posted: 2023-05-11
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a prospective, two arms, randomized (1:1), double blind, superiority study evaluating colchicine versus placebo administrated during six months among participants with acute myocarditis.
Primary purpose: TREATMENT

Brief summary: Myocarditis is an inflammatory disease of the heart, mostly caused by viruses. Patients with acute myocarditis are exposed to several complications: recurrence, ventricular arrhythmias (from 5 to 30%), heart failure (5-10%), death or heart transplantation (\< 4%). To date, there is no specific treatment for myocarditis. Patient management only focuses upon empirical optimal care of arrhythmia and heart failure.

There is a strong rationale for using colchicine in acute myocarditis:

* the IL1 (Interleukin1) pathway plays a detrimental role in acute myocarditis. NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome assembly, and subsequent IL-1beta production, are profoundly inhibited by colchicine.
* colchicine has been shown to improve cardiac outcomes in inflammatory cardiac disorders, including pericarditis, coronary artery disease, and post pericardiotomy syndrome.
* In murine model of CVB3-induced myocarditis (coxsackievirus B3), colchicine improved myocarditis through reduction of NLRP3 activity.
* Small case series with improvement of left ejection fraction in myocarditis following low-dose colchicine in addition to conventional heart failure therapy have been reported.

With its pleiotropic anti-inflammatory effect in the pro-inflammatory cascade, reducing the myocardial damage and cell death induced during myocarditis, colchicine has the potential to reduce the risk of heart failure and ventricular arrhythmias. Finally, colchicine is a drug widely available, at low cost, and has a long and well-known safety record.

Detailed description: This study is a prospective, randomized, multicenter, double blind, controlled versus placebo, phase III study in which two groups of participants are compared: a group treated with the experimental treatment Colchicine (in addition to standard of care therapy) compared to a control group that receive the corresponding placebo (in addition to standard of care therapy).

The inclusion visit takes place during the initial hospitalization stay. The study is presented to all patients presenting with acute myocarditis symptoms and inclusion criteria, hospitalized in participating centers.

Once eligible participants have been informed and signed their informed consent, they are randomized (1:1) by a centralized web system (IWRS) in the experimental group (Colchicine) or the control group (Placebo).

Participants receive then a numbered box with three months' treatment of Colchicine or placebo. The treatment must start at least within 72h after randomization. Another dispensing is performed during the three months' follow-up visit.

All randomized participants are followed during six months after the end of the treatment.

Eligibility criteria: Inclusion Criteria:

* Symptom onset of 21 days or less,
* Chest pain and/or Heart failure symptoms and/or palpitations
* Troponins superior to 99 percentile of reference value,
* Myocarditis diagnostic confirmation (by Contrast-Enhanced Cardiac Magnetic Resonance (CMR), according to the Lake Louise criteria (2009 or later),
* No evidence for ischemic heart disease on coronary angiography or coronary computed tomography angiography for patients with age superior to 40-year-old with one or more cardiovascular risk factor (hypertension, smoking, hypercholesterolemia, diabetes, personal or family history of coronary artery disease),
* Woman of child-bearing age with an effective contraception method according to the investigator for the duration of treatment and one month after,
* Man accepting effective contraception for the duration of treatment and one month after,
* Participant with affiliation to the French Health Care System "sécurité sociale",
* Written informed consent of the patient obtained.

Exclusion Criteria:

* Cardiogenic shock requiring inotropes or vasopressors (patients with inotropes discontinued for more than 24 hours can be enrolled)
* Giant cell myocarditis or eosinophilic myocarditis
* Acute coronary syndrome or known coronary stenosis superior to 50%
* Toxic cardiomyopathy
* Active chronic inflammatory disease, chronic active infection, evolving cancer
* A recent severe sepsis (7 days)
* Hypersensitivity to Investgational Medical Product's active substances (colchicine) or to any of the excipients (including lactose, sucrose, microcrystalline cellulose, colloidal silica, magnesium stearate, colourants : E127, Dual Red 40 )
* Any known contra-indication to CMR or associated contract products (claustrophobia; intra-ocular metal foreign bodies, clips such as cerebral, carotid, or aortic aneurysm, cochlear implants, any implant held in by magnet, non-MR compatible cardiac devices (pace maker or defibrillator); history of hypersensitivity to gadoteric acid or to gadolinium contrast agents or to meglumine),
* Chronic treatment with corticosteroids or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or immunosuppressant.
* Sarcoidosis
* Severe liver (Child Pugh C) or known renal dysfunction (known Glomerular Filtration Rate (GFR) less or equal to 30 ml/min according Cockroft),
* Cytopenia : hemoglobin less than 100 grams/L, white blood cell count less than 3.0 G/L, platelet count less than 100 G/L
* Major digestive disorders (chronic diarrhea, inflammatory disease of the digestive tract as uncontrolled ulcerative colitis or active Crohn disease)
* Immunosuppression, spinal cord aplasia
* Hemopathy
* Hypereosinophilia more than 0.5 G/L
* Pregnant or nursing women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive local laboratory test,
* Administration of any investigational drug or participation in another interventional trial, within 30 days before randomization,
* Participant under treatment having an interaction with colchicine \[macrolides (telithromycin, azithromycin, clarithromycin, dirithromycin, erythromycin, josamycin, midecamycin, roxithromycin), pristinamycin,, cyclosporine, verapamil, all protease inhibitors, telaprevir, CYP3A4 powerful inhibitors, azole antifungals, vitamin K antagonists\]
* Participant under legal protection: under guardianship (trusteeship or curatorship)

Primary outcomes:
measure: Extent of Late Gadolinium Enhancement (LGE) evaluated on Cardiac Magnetic Resonance (CMR)
timeFrame: Six months post-randomization
measure: Composite Clinical primary outcome
timeFrame: Six months post-randomization
Secondary outcomes:
measure: Safety of colchicine
timeFrame: Six months post-randomization
measure: Composite clinical secondary outcome
timeFrame: one year post-randomization
measure: Rate of heart failure at 6 months
timeFrame: Six months post-randomization
measure: Rate of acute myocarditis recurrence at 6 months
timeFrame: Six months post-randomization
measure: Rate of clinically relevant chest pain at 6 months
timeFrame: Six months post-randomization
measure: Rate of sustained ventricular arrhythmias at 6 months
timeFrame: Six months post-randomization
measure: Rate of left ventricular assistance at 6 months
timeFrame: Six months post-randomization
measure: Rate of heart transplantation at 6 months
timeFrame: Six months post-randomization
measure: Rate of cardiovascular death at 6 months
timeFrame: Six months post-randomization
measure: Rate of heart failure at 1 year
timeFrame: One year post-randomization
measure: Rate of acute myocarditis recurrence at 1 year
timeFrame: One year post-randomization
measure: Rate of clinically relevant chest pain at 1 year
timeFrame: One year post-randomization
measure: Rate of sustained ventricular arrhythmias at 1 year
timeFrame: One year post-randomization
measure: Rate of left ventricular assistance at 1 year
timeFrame: One year post-randomization
measure: Rate of heart transplantation at 1 year
timeFrame: One year post-randomization
measure: Rate of cardiovascular death at 1 year
timeFrame: One year post-randomization
measure: Left ventricular volume on Cardiac Magnetic Resonance (CMR)
timeFrame: Six months post-randomization
measure: Left ventricular volume on transthoracic echocardiography (TTE)
timeFrame: 6 months post-randomization
measure: Relative variation in Extent of late gadolinium enhancement (LGE) and edema
timeFrame: Six months post-randomization
measure: Tissue properties evaluated on Cardiac Magnetic Resonance (CMR)
timeFrame: Six months post-randomization
measure: Serum biomarkers
timeFrame: Six months post-randomization
measure: Specific Inflammatory markers
timeFrame: Six months post-randomization
measure: Ventricular premature complex (VPC) evaluated on Holter ElectroCardiogramm (ECG)
timeFrame: three months post-randomization
Other outcomes:
Locations:
city: Bron
country: France
facility: Unité de Soins Intensifs Cardiologiques - Hôpital Cardiovasculaire Louis Pradel
city: Paris
country: France
facility: Institut de Cardiologie - APHP Pitié Salpêtrière
Study officials:
affiliation: Cardiovascular hospital Louis Pradel
name: Thomas BOCHATON
role: STUDY_CHAIR
affiliation: Department of Cardiology - Pitié Salpêtrière Hospital
name: Mathieu KERNEIS
role: STUDY_DIRECTOR
References:
citation: Tschope C, Cooper LT, Torre-Amione G, Van Linthout S. Management of Myocarditis-Related Cardiomyopathy in Adults. Circ Res. 2019 May 24;124(11):1568-1583. doi: 10.1161/CIRCRESAHA.118.313578.
citation: Ammirati E, Cipriani M, Moro C, Raineri C, Pini D, Sormani P, Mantovani R, Varrenti M, Pedrotti P, Conca C, Mafrici A, Grosu A, Briguglia D, Guglielmetto S, Perego GB, Colombo S, Caico SI, Giannattasio C, Maestroni A, Carubelli V, Metra M, Lombardi C, Campodonico J, Agostoni P, Peretto G, Scelsi L, Turco A, Di Tano G, Campana C, Belloni A, Morandi F, Mortara A, Ciro A, Senni M, Gavazzi A, Frigerio M, Oliva F, Camici PG; Registro Lombardo delle Miocarditi. Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry. Circulation. 2018 Sep 11;138(11):1088-1099. doi: 10.1161/CIRCULATIONAHA.118.035319.
citation: Kyto V, Sipila J, Rautava P. Rate and patient features associated with recurrence of acute myocarditis. Eur J Intern Med. 2014 Dec;25(10):946-50. doi: 10.1016/j.ejim.2014.11.001. Epub 2014 Nov 7.
citation: Peretto G, Sala S, Rizzo S, Palmisano A, Esposito A, De Cobelli F, Campochiaro C, De Luca G, Foppoli L, Dagna L, Thiene G, Basso C, Della Bella P. Ventricular Arrhythmias in Myocarditis: Characterization and Relationships With Myocardial Inflammation. J Am Coll Cardiol. 2020 Mar 10;75(9):1046-1057. doi: 10.1016/j.jacc.2020.01.036.
citation: Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, Demarie D, Forno D, Ferro S, Maestroni S, Belli R, Trinchero R, Spodick DH, Adler Y; ICAP Investigators. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013 Oct 17;369(16):1522-8. doi: 10.1056/NEJMoa1208536. Epub 2013 Aug 31.