CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
- Conditions
- CardiomyopathiesMyocarditisInflammatory CardiomyopathyHeart FailureVentricular Arrythmia
- Interventions
- Other: Placebo
- Registration Number
- NCT06158698
- Lead Sponsor
- Niguarda Hospital
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 80
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Patients treated with placebo tablets. Colchicine Colchicine Patients treated with colchicine 0.5-1 mg (1 mg if tolerated) for 6 months.
- Primary Outcome Measures
Name Time Method Worsening imaging outcomes 6 months from randomization 1. Proportion of patients with LVEF reduction \>10%on echo/CMRI,
2. Proportion of patients with new areas of edema on CMRI or FDG-PET associated with an increase in the edema in the inflammatory lesion identified on baseline CMRI or FDG-PET.
Improvement of imaging outcome:
1. Proportion of patients with a reduction in edema on CMRI or FDG without new areas of edema AND normal high sensitivity troponin.
2. Proportion of patients with disappearance of edema on CMRI OR NO FDG uptake on PET Improvement of arrhythmic outcome:
1. Improvement of ARRHYTHMIC burden. Proportion of patients with a PVC burden reduction of 70% on the ECG ambulatory monitoring and no NSVT/SVT.Patients alive and free of any worsening features (clinical, arrhythmic burden and imaging outcome) AND that show at least one of the signs of improvements (IMAGING or ARRHYTMIC improvements). 6 months from randomization Clinical worsening (at least one of the following):
1. cardiac death
2. hospitalization for worsening HF or arrhythmic events,
3. Sustained ventricular tachycardia (SVT).
Worsening arrhythmic burden:
1. PVC burden increase of 50% on ECG ambulatory monitoring
2. Increase in NSVT of 30% compared with baseline
3. Any SVT.
- Secondary Outcome Measures
Name Time Method Time to HF or arrhythmic events 6 months from randomization Time to hospitalization for HF/VA or advanced AV block
Changes on ambulatory ECG monitoring 6 months from randomization Composite endpoint of NSVT OR increased burden of PVCs (\>5%) on 24-hour ECG ambulatory monitoring, performed at 6- months
Changes in Quality of life 6 months from randomization Changes in quality of life at 6 months follow up compared with baseline using 2 different questionnaires: the EoQ-5D-5L and KCCQ (CSS and OSS)
Need for immunosuppression 6 months from randomization Need to initiate an immunosuppressive drug
LVEF change on echocardiogram. 6 months from randomization Absolute change at 6 months from randomization of the LVEF on echocardiogram. Patients not performing echocardiography due to death, heart transplantation (HTx) will be counted as -10 point in the LVEF.
LVEF change on CMRI 6 months from randomization Absolute change at 6 months from randomization of the LVEF on CMRI when available. Patients not performing the CMRI due to death, HTx, LVAD implantation or device implantation after randomization will be counted as -10 point in the LVEF.
Mortality 6 months from randomization All-cause deaths
Evidence of dysfunction and/or dilation on CMRI 6 months from randomization Proportion of patients with LVEF\<55% AND/OR LV dilation on 6-month CMRI (CMRI clips will be centrally reviewed) or not performing the CMRI due to death, HTx, LVAD implantation or device implantation after randomization (i.e. ICD).
Clinical secondary endpoints 6 months from randomization Composite endpoint: (1) all-cause death or (2) HTx or (3) LVAD implantation, or (5) first rehospitalization due to HF or VA, or advanced atrioventricular (AV) block.
Trial Locations
- Locations (10)
Policlinico S.Orsola-Malpighi
🇮🇹Bologna, Emilia Romagna, Italy
Università degli studi della Campania L.Vanvitelli e Azienda Ospedaliera Specialistica dei Colli - Ospedale Monaldi
🇮🇹Napoli, Campania, Italy
Azienda Sanitaria Universitaria Integrata Giuliano Isontina, Trieste
🇮🇹Trieste, Friuli-Venezia Giulia, Italy
Presidio Ospedaliero Universitario "Santa Maria della Misericordia"
🇮🇹Udine, Friuli-Venezia Giulia, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹Roma, Lazio, Italy
IRCCS Ospedale San Raffaele
🇮🇹Milano, Lombardia, Italy
ASST Grande Ospedale Metropolitano Niguarda
🇮🇹Milano, Lombardia, Italy
Università Politecnica delle Marche e AOU Ospedali Riuniti Umberto I°-Lancisi-Salesi , Ancona
🇮🇹Ancona, Marche, Italy
Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino
🇮🇹Torino, Piemonte, Italy
ASL8 Arezzo San Donato Hospital
🇮🇹Arezzo, Toscana, Italy