| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| virus negative inflammatory cardiomyopathy |
| cardiomiopatia infiammatoria virus negativa |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inflammation of the hearth not virus-induced |
| Infiammazione del cuore non dovuta a virus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10007636 |
| E.1.2 | Term | Cardiomyopathy |
| E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The improvement in the ejection fraction = 10%. |
| L’obiettivo primario dello studio è il miglioramento della frazione di eiezione del ventricolo sinistro, come indice di funzionalità cardiaca) di una valore = 10%. |
|
| E.2.2 | Secondary objectives of the trial |
1) Reduction in mortality (cardiac death or heart transplantation) and in the rate of readmission to the hospital
2) Reduction of left ventricular end-diastolic volume
3) Evaluation of the modifications on cardiac histopathologic findings
3) Analysis of the variations of the immunologic profile (anti-heart autoantibodies, pattern Th1 or Th2 of the circulating lymphocytes)
4) Evaluation of the effect on the expression of the genes implicated in the cardiac reparative processes
5) Assessment of the level of cell death (apoptosis, necrosis, autophagy) and cell proliferation (ckit positive stem cells, cycling cardiomyocytes, lineage-committed cells).
|
1.Riduzione della mortalità e della percentuale di riammissione in ospedale
2.Riduzione volume telediastolico del ventricolo sinistro.
3.Miglioramento dello scompenso con riduzione della classe NYHA;
4.Valutazione del miglioramento del quadro istopatologico e ultrastrutturale del miocardio;
5.Analisi delle variazioni del profili immuno-infiammatorio (autoanticorpi anti-miocardio, quadro citochinico Th1/Th2 dei linfociti circolanti, caratterizzazione dell’infiltrato);
6.Valutazione dell’espressione genica miocardiocita-specifica dei geni correlati con i processi riparativi cardiaci;
7.Valutazione dei livelli di morte cellulare, apoptosi, autofagia e proliferazione miocardiocitaria (cellule c-kit+ e altre cellule staminali e precursori).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Men and women over the age of 18 years old
2) Signing of the informed consent
3) Chronic heart failure (NYHA class = II) lasting > 6 months
4) Dilation (left ventricular end-diastolic diameter more than 57 mm) and dysfunction (ejection fraction less than 45%) of the left ventricle.
5) Histologic (Dallas criteria) and immunohistochemical diagnosis of myocarditis, defined by the presence of at least 7/mm2 cluster of differentiation 3 (CD3) positive lymphocytes and/or at least 14 infiltrating leucocytes (LCA+ cells)/mm2 in the specimen, associated with necrosis of the adjacent cardiomyocytes.
6) Absence of cardiotropic viruses, as defined by polymerase chain reaction analysis for a wide panel of viral agents (i.e. adenovirus, enterovirus as echoviruses and coxsackie viruses, influenza virus A and B, HCV, herpes simplex virus 1 and 2, Cytomegalovirus, EBV, Parvovirus B19, Human Herpes Virus 6) and of bacterial agents (Borrelia burgdorferi) . The test must have been performed no more than 2 weeks prior to the inclusion in the study
7) Absence of valvular and/or coronary artery disease that can justify the severity of cardiac dysfunction
8) Negative blood pregnancy test in fertile females and usage of the highly effective method of contraception (hormonal or 2 barrier method of contraception). A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
9) Clinical progression of the disease despite anti-heart failure therapy from more than six months, including digitalis, diuretics, ACE inhibitors, and Carvedilol.
|
1. Uomini e donne con età maggiore di 18 anni
2. Firma del consenso informato
3. Scompenso cardiaco (classse NYHA maggiore di II) cronico (maggiore di 6 mesi)
4. Dilatazione (diametro telediastolico maggiore di 57 mm) e disfunzione (frazione di eiezione minore del 45%) del ventricolo sinistro
5. Evidenza istologica (criteri di Dallas) e immunoistochimica di miocardite (più di 7 linfociti CD3 positivi per mm2 e/o più di 14 leucociti per mm2 nei frammenti endomiocardici) associati a necrosi dei cardiomiociti adiacenti
6. Assenza di virus cardiotropi nel miocardio, definita in base alla negatività alla realTime PCR per un ampio panel di agenti virali (or i.e. adenovirus, enterovirus, influenza virus A e B, HCV, herpes simplex virus 1 and 2, Cytomegalovirus, EBV, Parvovirus B19, Human Herpes Virus 6) e batterici ((Borrelia burgdorferi) . La determinazione degli agenti infettivi deve essere eseguita non più di due settimane prima dell’inclusione nello studio..
7. Assenza di malattia coronarica e/o valvolare che possa giustificare la severità della disfunzione cardiaca.
8. Test di gravidanza negativo nelle donne fertili e uso di metodi di contraccezione altamente efficaci (metodi ormonali o almento 2 metodi di barriera). Una donna si considera con potenziale di concepimento (WOCBP) se è fertile, da dopo il menarca dino alla post-menopausa a meno che non sia permanentemente sterile. I metodi di sterilizzazione permanente includono l’isterectomia, la salpingectomia bilaterale e l’ovariectomia bilaterale.
9. Progressione clinica della malattia nonostante terapia anti scompenso cardiaco da più di sei mesi inclusa digitale, diuretici, ACE inibitori e carvedilolo
|
|
| E.4 | Principal exclusion criteria |
1. Recent (less than 6 months) onset of systolic heart failure, all known causes of heart failure (such as hypertension, significant coronary artery disease, valvular heart diseases),
2. Endocrine disease (tiroid, adrenal and hypophysis dysfunction),, significant renal disease (diseases causes creatinine clearance < 60 ml/min),, drug or alcohol abuse
3. Pregnancy and lactation
4. Therapy with steroids within the 6 months before the study
5. All contraindications of immunosuppressive therapy according to Summary of product characteristics (SmPC) of both investigational medicinal products
6. The refusal of a patient to participate in the study |
Recente (meno di 6 mesi) insorgenza di scompenso cardiaco
1) Cause note di scompenso cardiaco (ipertensione arteriosa, malattia coronarica significativa, malattie valvolari).
2) Malattie endocrine (disfunzione tiroidea, surrenalica o ipofisaria),, malattie renali significative (malattie che causano un a clearanced della creatinina < 60 ml/min),, abuso di droghe e alcol
3) Gravidanza o allattamento
4) Terapia con steroidi negli ultimi 6 mesi.
5) Controindicazioni al trattamento con steroidi e/o azatioprina in accordo con il sommario delle caratteristiche del prodotto (SmPC) di entrambi i farmaci.
6) Rifiuto del paziente a partecipare allo studio
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Improvement in left ventricular function, based on the enhancement of ejection fraction.
The patients will be defined as responders in presence of an improvement in ejection fraction of at least 10%.
|
| Miglioramento della frazione di eiezione del ventricolo sinistro, come indice di funzionalità cardiaca) di una valore = 10%. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the end of the study (six months) |
| Alla fine del protocollo di studio (sei mesi) |
|
| E.5.2 | Secondary end point(s) |
1) Reduction in mortality (cardiac death or heart transplantation) and in the rate of readmission to the hospital
2) Reduction of left ventricular end-diastolic volume.
3) Improvement in heart failure symptoms (evaluated as reduction in NYHA class)
4) Evaluation of the modifications on cardiac histopathologic findings
5) Analysis of the variations of the immunologic profile (anti-heart autoantibodies, pattern Th1 or Th2 of the circulating lymphocytes)
6) Evaluation of the effect on the expression of the genes implicated in the cardiac reparative processes
7) Assessment of the level of cell death (apoptosis, necrosis, autophagy) and cell proliferation (ckit positive stem cells, cycling cardiomyocytes, lineage-committed cells) in baseline cardiac dysfunction and in follow-up.
|
1. Riduzione della mortalità e della percentuale di riammissione in ospedale
2. Riduzione volume telediastolico del ventricolo sinistro.
3. Miglioramento dello scompenso con riduzione della classe NYHA;
4. Valutazione del miglioramento del quadro istopatologico e ultrastrutturale del miocardio;
5. Analisi delle variazioni del profili immuno-infiammatorio (autoanticorpi anti-miocardio, quadro citochinico Th1/Th2 dei linfociti circolanti, caratterizzazione dell’infiltrato);
6. Valutazione dell’espressione genica miocardiocita-specifica dei geni correlati con i processi riparativi cardiaci;
7. Valutazione dei livelli di morte cellulare, apoptosi, autofagia e proliferazione miocardiocitaria (cellule c-kit+ e altre cellule staminali e precursori).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of protocol (six months) |
| Alla fine del protocollo di studio (sei mesi) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The study duration from the First Patient First Visit (FPFV) will be 27 months .
|
| La durata dello studio dal primo paziente sarà 27 mesi |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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