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

Single-blinded Randomized Investigator-initiated Controlled Trial to Assess the Efficacy of Colchicine to Treat Patients With Cardiomyopathy With Myocarditis (Chronic Inflammatory Cardiomyopathy)

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 ventricular complexes (PVCs)/24 hours with FDG-PET imaging consistent with Infl-CMP, where a signal of benefit was observed in patients who received prednisone 40 mg for 3 months. The benefit was defined as a reduction in the PVC burden >80% and negative FDG-PET scan at follow-up. It must be noted that up to 24% of these cases had a diagnosis of sarcoidosis, where there is already an indication to therapy with steroids. In this study (MAVERIC registry) the improvement of patients treated with prednisone alone was 84% vs. 33% in patients not taking prednisone. As the investigators expect a lower effect of colchicine compared with prednisone but with a safer drug profile than prednisone, the investigators considered a theoretical optimal response in patients taking colchicine of 66%, while the investigators expected a similar optimal response in patients taking placebo as in the MAVERIC registry in patients not taking prednisone. Thus, considering an increase in the probability to reach the primary endpoint, defined as proportion of patients that are alive and free of any worsening (clinical, arrhythmic burden and imaging outcome) and that shows at least one of the signs of improvements (IMAGING or ARRHYTMIC improvements) at 6 months from 33% in the placebo arm to 66% in the colchicine therapy arm, the planned sample size of 80 patients (40 per group) will allow achieving a power of 0.80 with an overall type I error of 0.025 using one-sided Fisher's Exact test.

Endpoints will be analyzed according to the following principles:

1. Intention-to-treat (ITT) population: patients according to assigned randomized treatment arm.
2. Per Protocol (PP) population: only patients allocated to the colchicine therapy arm who took the drug for at least 4 months will be considered in the experimental group. Patients assigned to the colchicine therapy arm that will receive less than 4-month colchicine therapy will be excluded from this population. Likely, patients allocated to the optimal medical therapy with placebo will be included if they have taken the placebo therapy for at least 4 months. Patients allocated to the treatment or placebo that will receive any immunosuppressive agents (e.g. corticosteroids) for at least 1 month during the trial will be excluded from this population.
3. A sensitivity analysis will also be performed on the previously defined populations after excluding patients (1) with an implantable cardioverter defibrillator (ICD) before randomization (2) who underwent a ventricular ablation before randomization (3) who were diagnosed with a systemic autoimmune disorder or a histological diagnosis of eosinophilic myocarditis, cardiac sarcoidosis or giant cell myocarditis after the randomization.

REGISTRY - The main aim is to determine if patients with positive MCGV (+) Infl-CMP have a worse outcome compared with patients with negative MCGV (-) Infl-CMP in terms of recurrence of VA, including a high burden of PVCs or HF episodes or reduced improvement of ventricular function or persistence of myocardial inflammation on follow-up CMRI or FDG-PET. Furthermore, the investigators investigated characteristics that can help to identify patients with likely positive genetic tests among patients presenting with Infl-CMP, and variables that are independently associated with prognosis in patients with Infl-CMP. If patients have criteria to enter the registry, but not the trial, or (2) if do not consent to be randomized while they are willing to be followed in the registry, or (3) if the number of 80 patients is reached in the trial, even if the patients have the criteria to be included in the trial, these patients will enter the prospective registry. The foreseen number of the patients in the registry is 50-70 during the study period. To reach the objectives of the registry, deep phenotypical characterization of patients presenting with chronic Infl-CMP with VA and HF phenotypes will be performed in association with genetic testing.

TRANSLATIONAL STUDY - the investigators will perform translational experiments from the blood sample and endomyocardial biopsy (EMB) from patients recruited in the trial and the registry, if they consent. In particular, 50 patients (the first 25 with positive genetics and 25 with negative genetics) who agree to donate 18 mL of their blood will enter the translational study. From the blood, the investigators will get human-induced pluripotent stem cells (iPSC-CM) to unveil the molecular mechanisms that are responsible for the inflammatory response in the myocardium. As a control group, the investigators will involve the first 25 family members of the probands with the negative cardiac phenotype (FMPNCP) test that agree to be sampled for the same amount of blood. The hypothesis of these experiments is that a specific genetic background identified in patients with Inf-CMP is sufficient to induce an inflammatory myocardial response. Briefly, the investigators will generate tridimensional cardiac tissues (EHTs) using CMs derived from human-iPSC-CM from patients with MCGV(+) Infl-CMP versus MCGV(-) Infl- CMP and FMPNCP. EHTs and CMs will be subjected to specific mechanical, cellular, and pharmacological stimuli to unveil the molecular mechanisms that are responsible for the inflammatory response. The results of these experiments, together with the molecular analysis of EMBs could reveal novel molecular pathways that will be relevant to specific personalized therapeutic approaches.

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