Colchicine Versus Placebo in Acute Myocarditis Patients

Study Overview
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Brief Summary
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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
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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 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.

Official Title
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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

Conditions
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Acute Myocarditis

Intervention / Treatment
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* Drug: Colchicine Pill
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 with the presence of myocardial damage), 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) or all recent acute illness 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, pace maker, 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, Participant under legal protection: under guardianship (trusteeship or curatorship)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colchicine<br>Participant receive in addition to standard of care therapy, six months of Colchicine | Drug: Colchicine Pill<br>* Participant receive, in addition to standard of care therapy, six months of colchicine (at a dose of 0.5 mg twice daily, morning and evening) beginning maximum 72 hours post-randomization. The standard of care is defined according to the European consensus paper as follow: All participants without contraindication receive a betablockers, and heart failure ESC (European Society of Cardiology) guidelines directed medical therapies if LVEF < 50% (Left Ventricular Ejection Fraction), including ACE (Angiotensin-Converting Enzyme) inhibitors, diuretics if indicated. The choice of the dosage and the drug is left at the investigator decision. During the six months of the treatment administration, in case of severe adverse reaction (such as nausea and/or diarrhea during five days), a dose reduction could be considered by the investigator: half of the study protocol dose could be accepted (0.5 mg per day in the morning). In case of remaining adverse reactions, the study drug should be stopped.<br>* Other names: Colchicine;|
| Placebo Comparator: Placebo<br>Participant receive in addition to standard of care therapy, six months of placebo | Drug: Placebo<br>* Participant receive, in addition to standard of care therapy, six months of placebo (at a dose of 0.5 mg twice daily, morning and evening) beginning maximum 72 hours post-randomization. The standard of care is defined according to the European consensus paper as follow: All participants without contraindication receive a betablockers, and heart failure ESC (European Society of Cardiology) guidelines directed medical therapies if LVEF < 50% (Left Ventricular Ejection Fraction), including ACE (Angiotensin-Converting Enzyme) inhibitors, diuretics if indicated. The choice of the dosage and the drug is left at the investigator decision.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extent of Late Gadolinium Enhancement (LGE) evaluated on Cardiac Magnetic Resonance (CMR) | Extent of LGE (pourcentage of left ventricle mass) is evaluated (centralized reading by the Corelab) on CMR performed at six months and compared to baseline CMR (performed at the hospital admision or inclusion). The inclusion visit takes place during the initial hospitalization. | Six months post-inclusion | 
| Composite Clinical primary outcome | Composite Clinical primary outcome is assessed during the study period at six months on: the rate of rehospitalization for heart Failure or acute myocarditis recurrence; or the rate of clinically relevant recurrent chest pain (defined as leading to an unplanned/urgent consultation or hospitalization); or the rate of sustained ventricular arrhythmias; or the rate of left ventricular assistance; or the rate of heart transplantation; or the rate of cardiovascular death | Six months post-inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of colchicine | Safety of colchicine is defined as : Rate of Serious Adverse Events related to colchicine Rate of permanent treatment discontinuation Rate of diarrhea Rate of nausea and/or vomiting Rate of myelotoxicity (evaluated on Complete Blood Count) Renal function evaluated by creatinine level and creatinine clearance (MDRD) | Six months post-inclusion | 
| Composite clinical secondary outcome | Composite Clinical secondary outcome is assessed during the study period at one year on: Rate of rehospitalization for heart failure or acute myocarditis recurrence Rate of clinically relevant recurrent chest pain (defined as leading to an unplanned/urgent consultation or hospitalization) Rate of sustained ventricular arrhythmias Rate of left ventricular assistance or heart transplantation Rate of cardiovascular death | one year post-inclusion | 
| Left ventricular volume on Cardiac Magnetic Resonance (CMR) | Left Ventricular Ejection Fraction (LVEF), left ventricular end-diastolic and left ventricular end-systolic volumes are evaluated (centralized reading by the Corelab) on CMR performed at six months and compared to baseline CMR (performed at the hospital admision or inclusion). | Six months post-inclusion | 
| Left ventricular volume on transthoracic echocardiography (TTE) | Relative variation in Left ventricular ejection fraction (LVEF), end-diastolic volume and end-systolic volume between baseline and 6-months as determined by TTE. | 6 months post-inclusion | 
| Relative variation in Extent of late gadolinium enhancement (LGE) and edema | Relative variation in LGE and edema between baseline and six months determined centrally by the Corelab on the CMR | Six months post-inclusion | 
| Tissue properties evaluated on Cardiac Magnetic Resonance (CMR) | Cardiac magnetic resonance criteria: value of native T1 and T2 mapping (ms), pourcentage of extracellular volume | Six months post-inclusion | 
| Serum biomarkers | Serum biomarkers at hospital admission, 24h and 48h (after admission) and at six months: Troponin (I or T according to investigator), N-terminal pro-brain natriuretic peptide (NT-pro BNP), C-Reactiv Protein (CRP) and Creatin Kinase (CK) | Six months post-inclusion | 
| Specific Inflammatory markers | A biocollection, only for participating centers, is performed for specific Inflammatory markers : interleukin 6 (IL-6), interleukin 1 beta (IL-1bβ) and ST2 (or soluble interleukin 1 receptor-like 1). Patients undergo two blood samples of 4 mL at inclusion ; 24 hours and 48 hours after the inclusion visit, if the patient is still in hospital. | Inclusion visit and 24 hours and 48 hours post-inclusion visit | 
| Ventricular premature complex (VPC) evaluated on Holter ElectroCardiogramm (ECG) | VPC burden on Holter ECG performed during the hopsital consultation at three months | three months post-inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myocarditis, Inflammation, Colchicine