Heart Failure Clinical Trial
— CMP-MYTHiCOfficial title:
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.
Status | Recruiting |
Enrollment | 80 |
Est. completion date | May 2, 2028 |
Est. primary completion date | May 2, 2026 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
Italy | Università Politecnica delle Marche e AOU Ospedali Riuniti Umberto I°-Lancisi-Salesi , Ancona | Ancona | Marche |
Italy | ASL8 Arezzo San Donato Hospital | Arezzo | Toscana |
Italy | Policlinico S.Orsola-Malpighi | Bologna | Emilia Romagna |
Italy | ASST Grande Ospedale Metropolitano Niguarda | Milano | Lombardia |
Italy | IRCCS Ospedale San Raffaele | Milano | Lombardia |
Italy | Università degli studi della Campania L.Vanvitelli e Azienda Ospedaliera Specialistica dei Colli - Ospedale Monaldi | Napoli | Campania |
Italy | Fondazione Policlinico Universitario Agostino Gemelli IRCCS | Roma | Lazio |
Italy | Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino | Torino | Piemonte |
Italy | Azienda Sanitaria Universitaria Integrata Giuliano Isontina, Trieste | Trieste | Friuli-Venezia Giulia |
Italy | Presidio Ospedaliero Universitario "Santa Maria della Misericordia" | Udine | Friuli-Venezia Giulia |
Lead Sponsor | Collaborator |
---|---|
Niguarda Hospital | European Union, Mario Negri Institute for Pharmacological Research, Ministry of Health, Italy, University of Milano Bicocca |
Italy,
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Artico J, Merlo M, Delcaro G, Cannata A, Gentile P, De Angelis G, Paldino A, Bussani R, Ferro MD, Sinagra G. Lymphocytic Myocarditis: A Genetically Predisposed Disease? J Am Coll Cardiol. 2020 Jun 23;75(24):3098-3100. doi: 10.1016/j.jacc.2020.04.048. No abstract available. — View Citation
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Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | The primary aim of the REGISTRY is the proportion of patients with MCGV(+) Infl-CMP versus MCGV(-) Infl-CMP with more primary endpoints | We will measure the outcome of the patients in the registry as described in the TRIAL at the end of a minimum follow-up of 6 months.
The co-primary aim of the registry will be to the identify baseline variables that are independently associated with the above-mentioned 6-month endpoints. The patients who enter the registry are expected to follow an even longer follow-up of 2 The Registry endpoints pooling together patients included in the trial and registry. |
Minimum follow up at 6 months | |
Other | Differences in the results of in-vitro experiments between MCGV(+) vs. MCGV(-) Infl-CMP patients and between MCGV(+) Infl-CMP patients and family members of the probands with the negative cardiac phenotype (FMPNCP) | We will compare in-vitro experiments between MCGV(+) vs. Infl-CMP versus MCGV(-) Infl-CMP patients and between MCGV(+) Infl-CMP patients and family members of the probands with the negative cardiac phenotype (FMPNCP). Samples for the experiments will be from patients included in the trial and registry. | Minimum follow up at 6 months | |
Primary | 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). | Clinical worsening (at least one of the following):
cardiac death hospitalization for worsening HF or arrhythmic events, Sustained ventricular tachycardia (SVT). Worsening arrhythmic burden: PVC burden increase of 50% on ECG ambulatory monitoring Increase in NSVT of 30% compared with baseline Any SVT. |
6 months from randomization | |
Primary | Worsening imaging outcomes | Proportion of patients with LVEF reduction >10%on echo/CMRI,
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: Proportion of patients with a reduction in edema on CMRI or FDG without new areas of edema AND normal high sensitivity troponin. 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. |
6 months from randomization | |
Secondary | LVEF change on echocardiogram. | 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. | 6 months from randomization | |
Secondary | LVEF change on CMRI | 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. | 6 months from randomization | |
Secondary | Evidence of dysfunction and/or dilation on CMRI | 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). | 6 months from randomization | |
Secondary | Clinical secondary endpoints | 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. | 6 months from randomization | |
Secondary | Mortality | All-cause deaths | 6 months from randomization | |
Secondary | Time to HF or arrhythmic events | Time to hospitalization for HF/VA or advanced AV block | 6 months from randomization | |
Secondary | Changes on ambulatory ECG monitoring | Composite endpoint of NSVT OR increased burden of PVCs (>5%) on 24-hour ECG ambulatory monitoring, performed at 6- months | 6 months from randomization | |
Secondary | Changes in Quality of life | 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) | 6 months from randomization | |
Secondary | Need for immunosuppression | Need to initiate an immunosuppressive drug | 6 months from randomization |
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