CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine

Two-parallel groups randomized, single-blinded, multi-center phase III controlled trial in patients with chronic inflammatory cardiomyopathy to assess the efficacy of colchicine and associated prospective registry to assess the prognostic value of positive genetic testing in this population.

In a proportion of patients, myocarditis, an inflammatory injury of cardiomyocytes (CMs), can lead to chronic inflammatory cardiomyopathy (Infl-CMP) characterized by an increased risk of life-threatening ventricular arrhythmias (VA) or ventricular dysfunction and heart failure (HF). Most cases of myocarditis have a viral trigger or an autoimmune etiology, while genetic predisposition has been sporadically reported. Recent data point to a relevant role of genetics, with pathogenic genetic variants associated with dilated or arrhythmic cardiomyopathies found in 8-31% of patients with Infl-CMP and left ventricular (LV) systolic dysfunction. Occasionally, patients with myocarditis may have a positive family history of cardiomyopathy, or sudden cardiac death (SCD), which can lead to genetic testing for myopathic cardiac gene variants (MCGV). Small series showed the co-existence of myocarditis and MCGV in patients with dilated cardiomyopathy. In this complex background, it is still unclear whether targeting myocardial inflammation with immunomodulating drugs can ameliorate the outcome of these patients. TRIAL - The Investigators will conduct a Trial to assess whether in patients with Infl-CMP with VA or HF phenotype, colchicine compared with placebo can reduce myocardial inflammation improving the clinical condition of patients. In the trial both patients with positive MCGV and negative MCGV will be randomized, and the investigators check if the genetic background can affect the response to colchicine. The target of this pilot trial is to randomize 40 patients in each arm and have ideally 15 patients with MCGV(+) in each arm. The use of colchicine in our proposal of trial relies on the safety of colchicine, and the relatively low rate of side effects at low dosages. It has shown that colchicine performs its functions by inhibiting the activation of pore formation carried out by P2X2 and P2X7 receptors, that concur to the activation of the inflammasome, thus potentially targeting a specific cause observed in Infl-CMP. In a pilot, randomized, and single-blinded trial the investigators look at the immunomodulating effect of colchicine 0.5-1 mg vs. placebo in patients with Infl-CMP based on cardiac magnetic resonance imaging (CMRI) or fluorodeoxyglucose (FGD)-positron emission tomography (PET) scan with VA (including high premature ventricular complexes \[PVC\] burden), reduced LV ejection fraction (EF), or significantly increased levels of natriuretic peptides but without indication to immunosuppression (i.e., associated systemic autoimmune disorders) to assess whether colchicine can improve myocardial inflammation or decrease troponin release or the burden of PVCs or improve the clinical outcome (major VA, HF hospitalizations). The duration of the trial will be 6 months. The rationale of the pilot (CMP-MYTHiC CardioMyoPathy with MYocarditis THerapy with Colchicine) trial is based on a recent registry of 55 symptomatic patients with \>5000 premature ven Покажи пълното описание...

Inclusion Criteria Trial and Registry: * Males and females with Infl-CMP associated with VA (including high PVC burden), reduced LVEF, or significantly increased levels of natriuretic peptides. * Patients of 18 years or older * Evidence of myocardial inflammation on CMRI (using 2018 Lake Louis criteria) or FDG-PET performed in the 3 months before randomization to be included in the trial OR in the last 12 months before for the registry. * Presence of any of the following characteristics and if symptoms have been present for more than 1 month: * Mono-morphic or polymorphic PVC burden of ≥3000 in 24 hours, or NSVTs (defined as \>3 more consecutive beat lasting \<30 seconds) or evidence of sustained ventricular tachycardias (SVT). * Reduced LVEF on echocardiogram (\<50%) or on CMRI (\<60%)-. Increased N-terminal pro-B-type natriuretic peptide (NT- proBNP) concentration of 1000 pg/mL or more, or a B-type natriuretic peptide (BNP) concentration of 200 pg/mL or more * Persistence of increased high-sensitivity troponin levels above the upper reference limit (URL) after at least 2 months from the first assessment and at least a mono-morphic or polymorphic PVC burden of ≥1000 in 24 hours. Exclusion Criteria Registry: * Proven history of myocardial infarction with evidence of ischemic scar on echocardiogram or CMRI, * Significant flow-limiting coronary artery disease (stenosis above 50%) on invasive coronary angiography or computed tomography (CT) coronary angiography, * Cardiomyopathy attributed to toxins such as alcohol and illicit drugs, or to specific causes (i.e. amyloidosis or hypertrophic cardiomyopathy) * Known systemic autoimmune disorder (the exception will be for patients with systemic autoimmune disease or isolated cardiac sarcoidosis with a family history of cardiomyopathy, myocarditis, or arrhythmias, where overlap between an autoimmune event and a genetic background can occur). These patients will undergo genetic tests. Patients with autoimmune systemic disorders and isolated cardiac sarcoidosis with positive genetic tests for MCVG will be included in the registry. * Previous history of cardiac surgery for instance correction of congenital heart disease or a valve repair/replacement * Known chronic infective disease, such as HIV infection or tuberculosis * Participants involved in another clinical trial, defined by the participation in a clinical trial in which an investigational drug was administered in the 30 days prior to screening, or 5 half-lives of the study drug, whichever is longer; * Any other significant disease or disorder which (expected life expectancy \<12 months), in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial or the participant's ability to participate in the trial. Exclusion Criteria Trial : * Proven history of myocardial infarction with evidence of ischemic scar on echocardiogram or CMRI, * Significant flow-limiting coronary artery disease (stenosis above 50%) on invasive coronary angiography or computed tomography (CT) coronary angiography, * Cardiomyopathy attributed to toxins such as alcohol and illicit drugs, or to specific causes (i.e. amyloidosis or hypertrophic cardiomyopathy) * Known systemic autoimmune disorder (the exception will be for patients with systemic autoimmune disease or isolated cardiac sarcoidosis with a family history of cardiomyopathy, myocarditis, or arrhythmias, where overlap between an autoimmune event and a genetic background can occur). These patients will undergo genetic tests. Patients with autoimmune systemic disorders and isolated cardiac sarcoidosis with positive genetic tests for MCVG will be included in the registry. * Previous history of cardiac surgery for instance correction of congenital heart disease or a valve repair/replacement * Known chronic infective disease, such as HIV infection or tuberculosis * Participants involved in another clinical trial, defined by the participation in a clinical trial in which an investigational drug was administered in the 30 days prior to screening, or 5 half-lives of the study drug, whichever is longer; * Any other significant disease or disorder which (expected life expectancy \<12 months), in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial or the participant's ability to participate in the trial. * Women with childbearing potential (this exclusion criterion is due to insufficient human information regarding the embryofoetal risk with colchicine) * Current symptomatic atrial arrhythmias (including persistent atrial fibrillation) associated with LV dysfunction, * Advance heart failure (NYHA III or need for inotropes including levosimendan), or recurrent VA despite previous catheter ablation, * Known systemic autoimmune disorder or other conditions at the time of randomization where immunosuppression is assumed useful (i.e. cardiac sarcoidosis), * Patients already on chronic immunosuppressive therapies (including colchicine) or in whom immunosuppressive therapy is deemed necessary * Contraindication to colchicine, including allergies to this medication and its excipients (i.e., lactose and sucrose), * Impaired renal function (eGFR\<30 ml/min/1.73m2), * Known history of hepatic cirrhosis or transaminase levels at baseline \> x3-fold the URL * Patients with peripheral eosinophilia (eosinophil count \>10% of the leukocytes) or known hypereosinophilic syndrome at the time of randomization. * Severe gastrointestinal insufficiency (for instance, malabsorption syndrome, severe chronic diarrhea) * Women during breastfeeding