Acute Myocarditis
Conditions
Keywords
Myocarditis, Inflammation, Colchicine
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.
Interventions
DRUGColchicine Pill
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.
DRUGPlacebo
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.
Sponsors
Assistance Publique - Hôpitaux de Paris
Hospices Civils de Lyon
Fonds de Dotation ACTION
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Symptom onset of 28 days or less, * Myocarditis initially presenting with chest pain and/or Heart failure symptoms and/or palpitations * Troponins superior to 99 percentile of reference value, at any time between admission and inclusion * 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, history of hypersensitivity to gadoteric acid or to gadolinium contrast agents or to meglumine). Patients with an implantable cardioverter-defibrillator (ICD) or pacemaker (PM) are also excluded due to the risk of imaging artifacts, which may compromise the reliable quantification of late gadolinium enhancement (LGE). * Chronic treatment with corticosteroids or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or high-dose aspirin 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 between admission and inclusion (within 7 days) * 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 between admission and inclusion * 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Extent of Late Gadolinium Enhancement (LGE) evaluated on Cardiac Magnetic Resonance (CMR) | Six months post-randomization | 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. |
| Composite Clinical primary outcome | Six months post-randomization | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety of colchicine | Six months post-randomization | 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) |
| Composite clinical secondary outcome | one year post-randomization | 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 |
| Rate of heart failure at 6 months | Six months post-randomization | Rate of heart failure is a component of the composite clinical secondary endpoint. It is assessed at 6 months. |
| Rate of acute myocarditis recurrence at 6 months | Six months post-randomization | Rate of acute myocarditis recurrence is a component of the composite clinical secondary endpoint. It is assessed at 6 months. |
| Rate of clinically relevant chest pain at 6 months | Six months post-randomization | 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. |
| Rate of sustained ventricular arrhythmias at 6 months | Six months post-randomization | Rate of sustained ventricular arrhythmias is a component of the composite clinical secondary endpoint. It is assessed at 6 months. |
| Rate of left ventricular assistance at 6 months | Six months post-randomization | Rate of left ventricular assistance is a component of the composite clinical secondary endpoint. It is assessed at 6 months. |
| Rate of heart transplantation at 6 months | Six months post-randomization | Rate of heart transplantation is a component of the composite clinical secondary endpoint. It is assessed at 6 months. |
| Rate of cardiovascular death at 6 months | Six months post-randomization | Rate of cardiovascular death is a component of the composite clinical secondary endpoint. It is assessed at 6 months. |
| Rate of heart failure at 1 year | One year post-randomization | Rate of heart failure is a component of the composite clinical secondary endpoint. It is assessed at 1 year. |
| Rate of acute myocarditis recurrence at 1 year | One year post-randomization | Rate ofacute myocarditis recurrence is a component of the composite clinical secondary endpoint. It is assessed at 1 year. |
| Rate of clinically relevant chest pain at 1 year | One year post-randomization | 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 1 year. |
| Rate of sustained ventricular arrhythmias at 1 year | One year post-randomization | Rate of sustained ventricular arrhythmias is a component of the composite clinical secondary endpoint. It is assessed at 1 year. |
| Rate of left ventricular assistance at 1 year | One year post-randomization | Rate of left ventricular assistance is a component of the composite clinical secondary endpoint. It is assessed at 1 year. |
| Rate of heart transplantation at 1 year | One year post-randomization | Rate of heart transplantation is a component of the composite clinical secondary endpoint. It is assessed at 1 year. |
| Rate of cardiovascular death at 1 year | One year post-randomization | Rate of cardiovascular death is a component of the composite clinical secondary endpoint. It is assessed at 1 year. |
| Left ventricular volume on Cardiac Magnetic Resonance (CMR) | Six months post-randomization | 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). |
| Left ventricular volume on transthoracic echocardiography (TTE) | 6 months post-randomization | Relative variation in Left ventricular ejection fraction (LVEF) between baseline and 6-months as determined by TTE. |
| Relative variation in Extent of late gadolinium enhancement (LGE) and edema | Six months post-randomization | Relative variation in LGE and edema between baseline and six months determined centrally by the Corelab on the CMR |
| Tissue properties evaluated on Cardiac Magnetic Resonance (CMR) | Six months post-randomization | Cardiac magnetic resonance criteria: value of native T1 and T2 mapping (ms), pourcentage of extracellular volume |
| Serum biomarkers | Six months post-randomization | Serum biomarkers during the hospital period (eg: admission, 24h and 48h (after admission), inclusion or discharge) 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) |
| Specific Inflammatory markers | Six months post-randomization | 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. |
| Ventricular premature complex (VPC) evaluated on Holter ElectroCardiogramm (ECG) | three months post-randomization | VPC burden on Holter ECG performed during the hopsital consultation at three months |
Countries
France
Contacts
CONTACTThomas BOCHATON
CONTACTJulia CANTERINI
STUDY_CHAIRThomas BOCHATON
Cardiovascular hospital Louis Pradel
STUDY_DIRECTORMathieu KERNEIS
Department of Cardiology - Pitié Salpêtrière Hospital
Outcome results
None listed