Colchicine Versus Placebo in Acute Myocarditis Patients

Phase 3RecruitingNCT05855746

Assistance Publique - Hôpitaux de Paris300 enrolled

Overview

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.

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.

Study Type

Interventions

Colchicine PillDRUG

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.

PlaceboDRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

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.

Time frame: Six months post-randomization

Composite Clinical primary outcome

Composite Clinical primary outcome is assessed during the study period at six months on: * the rate of heart Failure or acute myocarditis recurrence; * or the rate of clinically relevant chest pain (defined as leading to an unplanned/urgent consultation or hospitalization or requiring an additional treatment); * 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

Time frame: Six months post-randomization

Secondary Outcomes

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)

Time frame: Six months post-randomization

Composite clinical secondary outcome

Composite Clinical secondary outcome is assessed during the study period at one year on: * Rate of heart failure or acute myocarditis recurrence * Rate of clinically relevant chest pain (defined as leading to an unplanned/urgent consultation or hospitalization or requiring an additional treatment) * Rate of sustained ventricular arrhythmias * Rate of left ventricular assistance or heart transplantation * Rate of cardiovascular death

Time frame: one year post-randomization

Rate of heart failure at 6 months

Rate of heart failure is a component of the composite clinical secondary endpoint. It is assessed at 6 months.

Time frame: Six months post-randomization

Rate of acute myocarditis recurrence at 6 months

Rate of acute myocarditis recurrence is a component of the composite clinical secondary endpoint. It is assessed at 6 months.

Time frame: Six months post-randomization

Rate of clinically relevant chest pain at 6 months

Rate of clinically relevant chest pain (defined as leading to an unplanned/urgent consultation or hospitalization or requiring an additional treatment) is a component of the composite clinical secondary endpoint. It is assessed at 6 months.

Time frame: Six months post-randomization

Rate of sustained ventricular arrhythmias at 6 months

Rate of sustained ventricular arrhythmias is a component of the composite clinical secondary endpoint. It is assessed at 6 months.

Time frame: Six months post-randomization

Rate of left ventricular assistance at 6 months

Rate of left ventricular assistance is a component of the composite clinical secondary endpoint. It is assessed at 6 months.

Time frame: Six months post-randomization

Rate of heart transplantation at 6 months

Rate of heart transplantation is a component of the composite clinical secondary endpoint. It is assessed at 6 months.

Time frame: Six months post-randomization

Rate of cardiovascular death at 6 months

Rate of cardiovascular death is a component of the composite clinical secondary endpoint. It is assessed at 6 months.

Time frame: Six months post-randomization

Rate of heart failure at 1 year

Rate of heart failure is a component of the composite clinical secondary endpoint. It is assessed at 1 year.

Time frame: One year post-randomization

Rate of acute myocarditis recurrence at 1 year

Rate ofacute myocarditis recurrence is a component of the composite clinical secondary endpoint. It is assessed at 1 year.

Time frame: One year post-randomization

Rate of clinically relevant chest pain at 1 year

Time frame: One year post-randomization

Rate of sustained ventricular arrhythmias at 1 year

Rate of sustained ventricular arrhythmias is a component of the composite clinical secondary endpoint. It is assessed at 1 year.

Time frame: One year post-randomization

Rate of left ventricular assistance at 1 year

Rate of left ventricular assistance is a component of the composite clinical secondary endpoint. It is assessed at 1 year.

Time frame: One year post-randomization

Rate of heart transplantation at 1 year

Rate of heart transplantation is a component of the composite clinical secondary endpoint. It is assessed at 1 year.

Time frame: One year post-randomization

Rate of cardiovascular death at 1 year

Rate of cardiovascular death is a component of the composite clinical secondary endpoint. It is assessed at 1 year.

Time frame: One year post-randomization

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).

Time frame: Six months post-randomization

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.

Time frame: 6 months post-randomization

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

Time frame: Six months post-randomization

Tissue properties evaluated on Cardiac Magnetic Resonance (CMR)

Cardiac magnetic resonance criteria: value of native T1 and T2 mapping (ms), pourcentage of extracellular volume

Time frame: Six months post-randomization

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)

Time frame: Six months post-randomization

Specific Inflammatory markers

Analysis of specific Inflammatory markers only for participating centers of biocollection at six months post-randomization versus baseline (inclusion; 24 hours and 48 hours post-inclusion) : 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; and at 6 months post-randomization.

Time frame: Six months post-randomization

Ventricular premature complex (VPC) evaluated on Holter ElectroCardiogramm (ECG)

VPC burden on Holter ECG performed during the hopsital consultation at three months

Time frame: three months post-randomization

Colchicine Versus Placebo in Acute Myocarditis Patients

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts