Rationale and study design of the multicenter randomized control trial CardioMyoPathy with MYocarditis THerapy with Colchicine: the CMP-MYTHiC trial

Background Most patients with inflammatory cardiomyopathies are diagnosed non-invasively by cardiac magnetic resonance imaging (CMRI) or less frequently by fluorodeoxyglucose-positron emission tomography (FDG-PET) scan. No specific immunosuppressive treatments are recommended for patients with chronic inflammatory cardiomyopathy with left ventricular (LV) systolic dysfunction/heart failure (HF) or arrhythmic phenotype and evidence of inflammation on imaging. Purpose to assess the efficacy of colchicine (0.5 mg in patients of <70 kg or 1 mg if ≥70 kg) administered for 6 months on top of optimized medical therapy in patients with inflammatory cardiomyopathy. Methods A multicenter single-blinded randomized controlled trial that screens patients diagnosed with inflammatory cardiomyopathy based on CMRI or FDG-PET scan is ongoing. Eligibility is defined by the presence >1 month of: (1) high burden of premature ventricular complexes (PVCs) on 24-hour ECG ambulatory monitoring or presence of non-sustained ventricular tachycardia (NSVT), or sustained ventricular tachycardia (SVT), (2) LV ejection fraction (EF)<50% on echocardiogram or <60% on CMRI, or (3) increased levels of natriuretic peptides. Key exclusion criteria: coronary artery disease, cardiomyopathy due to specific causes, known systemic autoimmune disorders where immunosuppression may be beneficial, advanced HF, ongoing immunosuppressive therapies. Assuming an increase in the likelihood of reaching the primary endpoint at 6 months from 33% in the placebo group to 66% in the colchicine group, a 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 (Figure). Results To assess the efficacy of colchicine, the primary endpoint of the trial is the proportion of patients who are alive free from any clinical worsening, arrhythmic burden or adverse imaging outcomes, and who demonstrate improvement in imaging or arrhythmic outcomes. Clinical worsening is defined as: cardiac death, HF hospitalization or arrhythmic events. Worsening arrhythmic burden is defined as a 50% increase in the PVC burden, a 30% increase in NSVT compared to baseline, or SVT. Worsening imaging outcomes are defined as a reduction in LVEF>10% or the appearance of new areas of edema on CMRI or FDG-PET scan. Improvement in imaging outcome is defined as (1) reduction in edema on CMRI or FDG uptake and no troponin increase or (2) the complete resolution of edema. Improvement in the arrhythmic outcomes is defined as (1) a 70% reduction in PVC burden with no NSVT or SVT. Currently, there are 10 active centers, and 16 (20%) patients out of 80 have been randomized since December 2023. The trial is expected to be completed by the end of 2026. Conclusion The results of the CMP-MYTHiC trial can define the role of colchicine in treating patients with inflammatory cardiomyopathy who show evidence of inflammation on CMRI or FDG-PET.