| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute heart failure |
| insufficienza cardiaca acuta |
|
| 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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000803 |
| E.1.2 | Term | Acute heart failure |
| 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 primary objective of the study is to evaluate the effect of 48 hours of intravenous (IV) omecamtiv mecarbil compared with placebo on dyspnea in subjects with left ventricular systolic dysfunction hospitalized for acute heart failure (AHF). |
| L'obiettivo primario dello studio consiste nel valutare l'effetto sulla dispnea di omecamtiv mecarbil rispetto al placebo somministrato per 48 ore per via endovenosa, in soggetti con disfunzione sistolica del ventricolo sinistro ricoverati per insufficienza cardiaca acuta. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the safety and tolerability of 3 dose levels of IV omecamtiv mecarbil compared with placebo in subjects with left ventricular systolic dysfunction hospitalized for AHF. To evaluate the effects of 48 hours treatment with IV omecamtiv mecarbil on additional measures of dyspnea, patient global assessment (PGA), change in N-terminal pro brain-type natriuretic peptide (NT-pro BNP) and short-term clinical outcomes. To characterize pharmacokinetics of omecamtiv mecarbil, including metabolites M1 and M3, following IV infusion and to evaluate the relationship between omecamtiv mecarbil plasma concentration and echocardiographic parameters in subjects with acute heart failure. |
| Valutare sicurezza ed efficacia dei tre livelli di dosaggio di omecamtiv mecarbil e.v. rispetto al placebo in soggetti con disfunzione sistolica del ventricolo sinistro ricoverati per insufficienza cardiaca acuta. • Stabilire gli effetti della terapia di 48 ore con omecamtiv mecarbil e.v. in base a diverse valutazioni sulla dispnea, dalla valutazione globale del paziente (PGA), dalle modifiche dell'NT-pro BNP (frazione plasmatica N-terminale del precursore peptidico natriuretico cerebrale) e dagli esiti clinici a breve termine • Definire la farmacocinetica di omecamtiv mecarbil, compresi i metaboliti M1 e M3, dopo infusione e.v. e valutare il rapporto esistente tra la concentrazione plasmatica di omecamtiv mecarbil e i parametri ecocardiografici in soggetti con insufficienza cardiaca acuta |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PHARMACOGENETIC:
Vers:am.1
Date:2011/01/24
Title:
Objectives:
PHARMACOKINETIC/PHARMACODYNAMIC:
Vers:am.1
Date:2011/01/24
Title:
Objectives:
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FARMACOGENETICA:
Vers:am.1
Data:2011/01/24
Titolo:/
Obiettivi:All subjects will be invited to participate in a biomarker and pharmacogenetic substudy. The objectives are: To investigate the effects of genetic variation in liver enzymes on omecamtiv mecarbil and metabolite plasma concentrations and/or subject response To investigate potential biomarker development by biochemical analysis of blood and urine samples
FARMACOCINETICA/FARMACODINAMICA:
Vers:am.1
Data:2011/01/24
Titolo://
Obiettivi:At a number of sites, subjects will be invited to participate in a PK/PD substudy with additional blood sampling for PK analysis and with echocardiography imaging. The objective of the PK/PD sub-study is to provide data to characterize the phramacokientics of omecamtiv mecarbil after intravenous infusion doses and to correlate omecamtiv mecarbil plasma concentration and echocardiographic parameters in subjects with acute heart failure
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| E.3 | Principal inclusion criteria |
| Subject or subject’s legally acceptable representative has provided informed consent. Male or female ≥ 18 years of age at the time of randomization. Current hospitalization for a primary reason of worsening heart failure (determined by the investigator) and requiring IV therapy for heart failure. History of chronic heart failure (defined as requiring treatment for heart failure for a minimum of 30 days before hospitalization).History of left ventricular ejection fraction (LVEF) ≤ 35% (echocardiogram, radionuclide ventriculography, cardiac magnetic resonance imaging, or contrast ventriculography) within 12 months before randomization and without a subsequent intervening value of > 35%. Dyspnea at rest due to heart failure at least 2 hours after having received ≥ 40 mg intravenous furosemide (or equivalent dose of an alternative loop diuretic) during the current hospitalization; dyspnea should be present at randomization. Brain-type natriuretic peptide (BNP) ≥ 400 pg/mL or NT-proBNP ≥ 1600 pg/mL during screening (BNP ≥ 600 pg/mL or NT-proBNP ≥ 2400 pg/mL if the subject has atrial fibrillation at presentation). Female subjects, if not postmenopausal or sterilized, must have a negative pregnancy test, must not be breastfeeding and must agree to abstain from sexual intercourse or use highly effective methods of birth control during treatment and for 5 days following the last dose of investigational product. Highly effective methods of birth control include: sterilization, birth control pills, Depo-Provera injections, or contraceptive implants. Postmenopausal female is defined as 12 continuous months of spontaneous amenorrhea. Male subjects with a partner of childbearing potential must agree to inform their partner of their participation in this clinical study and, during treatment and for 5 days after the last dose of investigational product, to abstain from sexual intercourse or use highly effective methods of birth control, such as: vasectomy or a condom in combination with hormonal birth control or barrier methods used by the woman. For male subjects with pregnant partners, sexual abstinence or a condom must be used for 5 days after the last dose. If participating in the PK/PD substudy, subject must currently be in sinus rhythm. |
| • consenso informato da parte del soggetto o di un suo rappresentante legale • uomini o donne ≥ 18 anni di eta' alla randomizzazione • ricovero ospedaliero in corso dovuto principalmente al peggioramento dell’insufficienza cardiaca (stabilito dallo sperimentatore) che necessiti di terapia e.v. per trattare l’insufficienza cardiaca • storia di insufficienza cardiaca cronica (che ha richiesto un trattamento per insufficienza cardiaca per un minimo di 30 giorni precedenti al ricovero ospedaliero) • Storia di riduzione della frazione di eiezione ventricolare sinistra (LVEF) ≤ 35% (evidenziata tramite ecocardiogramma, ventricolografia con radionuclide, risonanza magnetica cardiaca per immagini, o ventricolografia eseguita con mezzo di contrasto) nei 12 mesi precedenti la randomizzazione senza un successivo valore > 35% • Dispnea a riposo dovuta a insufficienza cardiaca almeno 2 ore dopo la somministrazione per via endovenosa di ≥ 40 mg di furosemide (o di dose equivalente di un diuretico dell'ansa alternativo); lo stato di dispnea deve essere presente al momento della randomizzazione • Peptide natriuretico cerebrale (BNP) ≥ 400 pg/ml o NT-proBNP ≥ 1600 pg/ml allo screening (BNP ≥ 600 pg/ml o NT-proBNP ≥ 2400 pg/ml se il soggetto presenta, all'arrivo, fibrillazione atriale) • Nel caso in cui il soggetto partecipi al sottostudio di PK/PD, deve essere in ritmo sinusale I soggetti di sesso femminile, se non sono in post menopausa (≥ 12 mesi di amenorrea spontanea) o se non sono sterili, devono avere il test di gravidanza negativo, non devono allattare e devono accettare di astenersi da rapporti sessuali o utilizzare metodi di contraccezione altamente efficaci durante la terapia e nei 5 giorni successivi all'assunzione dell'ultima dose del prodotto sperimentale. I metodi di contraccezione altamente efficaci comprendono: sterilizzazione, pillole contraccettive, iniezioni di Depo-Provera o impianti contraccettivi. I soggetti di sesso maschile che hanno una partner potenzialmente fertile devono acconsentire ad informare tale partner della loro partecipazione a questo studio clinico ed astenersi, nel corso della terapia e nei 5 giorni successivi all'assunzione dell'ultima dose del prodotto sperimentale, da rapporti sessuali, o utilizzare metodi di contraccezione altamente efficaci come: vasectomia o profilattico congiuntamente ai sistemi contraccettivi ormonali o ai metodi di barriera utilizzati dalle donne. I soggetti di sesso maschile le cui partner siano in stato di gravidanza devono, nei 5 giorni successivi all'assunzione dell'ultima dose, astenersi da pratiche sessuali o utilizzare un profilattico. |
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| E.4 | Principal exclusion criteria |
| Disease-specific. Receiving IV vasopressor (excluding dopamine ≤ 5 μg/kg/min), inotropic or mechanical (eg, intra-aortic balloon pump counterpulsation) support between admission to the hospital and randomization. Subject has a pulmonary artery catheter. Subject requires endotracheal mechanical ventilation. Subject has acute coronary syndrome. Within 6 weeks prior to enrollment: cardiac resynchronization therapy (CRT) or implantable cardioverter defibrillator (ICD) implantation, hospitalization for acute coronary syndrome, coronary revascularization, transient ischemic attack or stroke, sustained ventricular arrhythmia, or major surgery. Likely to receive within 6 months after randomization, in the opinion of the investigator, planned revascularization, implantation of ICD, or CRT, ventricular assist device, continuous inotropic therapy, intermittent out-patient inotropic therapy, hospice care, or cardiac transplant. Severe aortic or mitral stenosis or heart failure primarily due to valvular heart disease or clinically significant valvular heart disease that might lead to surgical correction within 6 months of randomization. Hypertrophic obstructive cardiomyopathy, active myocarditis, or constrictive pericarditis, or clinically significant congenital heart disease. Chronic antiarrhythmic therapy, with the exception of amiodarone. Routinely scheduled outpatient IV infusions for HF (eg, inotropes, vasodilators [eg, nesiritide], diuretics) or routinely scheduled ultrafiltration. Evidence of digitalis intoxication. Other medical conditions Blood pressure (BP) > 160/100 mm Hg, systolic BP (SBP) < 90 mm Hg, or heart rate (HR) > 110 bpm or HR < 60 bpm at screening and confirmed by a repeat assessment. Estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease (MDRD) equation < 30 mL/min/1.73m2 at screening. Severe, concomitant non-cardiovascular disease that is expected to reduce life expectancy to less than 1 year. Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal) or receiving renal replacement therapy by dialysis. Receiving or has received chemotherapy and/or radiation therapy for treatment of a malignancy within 6 months prior to randomization or clinical evidence of current malignancy, with the following exceptions: localized basal or squamous cell carcinoma of the skin or cervical intraepithelial neoplasia. Untreated hypothyroidism or hyperthyroidism, adrenal insufficiency, active vasculitis due to collagen vascular disease. Hepatic impairment defined by a total bilirubin ≥ 2 times the upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 5 times ULN at screening. General or other Previously received omecamtiv mecarbil.Currently enrolled in another investigational heart failure device or drug study, or less than 30 days since ending another investigational heart failure device or drug study, or receiving other investigational agent(s) for heart failure. Recent (within 3 months) history of alcohol or illicit drug abuse based on self-report. Known sensitivity to any of the products to be administered during dosing. Subject previously has entered this study. Subject will not be available for protocol-required study visits, to the best of the subject’s or investigator’s knowledge. Any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures. |
| Insufficienza cardiaca di varia natura ed altri criteri di esclusione di natura cardiovascolare comprendono, ma non sono limitati a , ricorso a vaso-soppressori per via endovenosa (con l'esclusione della dopamina ≤ 5 mcg/kg/min), terapia inotropica o supporti circolatori di tipo meccanico (ad es., contropulsazione aortica con palloncino) tra l'ammissione in ospedale e la randomizzazione, catetere arterioso polmonare, ventilazione meccanica mediante tubo endotracheale, sindrome coronarica acuta in evoluzione, o una delle seguenti condizioni riportate nelle 6 settimane precedenti all'arruolamento: terapia di resincronizzazione cardiaca (CRT) o defibrillatore cardiaco impiantabile (ICD), ricovero per sindrome coronarica acuta, rivascolarizzazione coronarica, attacco ischemico transitorio o ictus, aritmia ventricolare sostenuta, o chirurgia maggiore. Sono inoltre esclusi i soggetti che potrebbero sottoporsi entro 6 mesi dalla randomizzazione a: rivascolarizzazione programmata, defibrillatore cardiaco impiantabile (ICD) o terapia di resincronizzazione cardiaca (CRT), ventricolo artificiale, terapia inotropica continua, terapia inotropica intermittente ambulatoriale, cure in luoghi di lungodegenza, o trapianto cardiaco. Non e' ammesso che i soggetti presentino gravi stenosi aortiche o mitrali, ne' insufficienza cardiaca dovuta principalmente a cardiopatie valvolari talmente gravi da determinare il ricorso ad intervento chirurgico entro 6 mesi dalla procedura di randomizzazione. Altri criteri di esclusione sono la pressione arteriosa (BP) > 160/100 mm Hg, la pressione arteriosa sistolica (SBP) < 90 mm Hg, la frequenza cardiaca (HR) o > 110 o < 60 bpm, velocita' stimata di filtrazione glomerulare (eGFR) calcolata in base all'equazione Modificata della Dieta per Malattia Renale (MDRD) < 30 ml/min/1.73m2 durante le procedure di screening, grave patologia non cardiovascolare che si prevede possa ridurre l'aspettativa di vita a meno di 1 anno, qualsiasi trapianto a carico di un organo maggiore (ovvero, polmone, fegato, cuore, midollo spinale, rene), ricorso a terapie di sostituzione renale mediante dialisi, bilirubina totale ≥ 2 volte il limite massimo rispetto alla norma (ULN) o alanina aminotransferasi (ALT) o aspartato aminotransferasi (AST) ≥ 5 volte rispetto alla norma (ULN) nel corso dello screening. Non sono ammessi i soggetti che, nei 6 mesi precedenti la randomizzazione, siano stati esposti a chemioterapia o che stiano effettuando cicli di chemioterapia e/o radioterapia per la cura di un tumore, ne' i soggetti che dispongono di prove cliniche attestanti l'esistenza di un tumore, ad eccezione di quanto espresso nella Sezione 4.2 del protocollo. Per un elenco completo dei criteri di eleggibilita', si prega di far riferimento alle Sezioni 4.1 e 4.2 del protocollo. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is dyspnea symptom response defined as follows: minimally, moderately or markedly better by 7-point Likert scale at 6 hours after investigational product initiation, AND moderately or markedly better at 24 and 48 hours after investigational product initiation without worsening heart failure event or death by 48 hours. |
| L'endpoint primario e' la risposta sintomatologica alla dispnea valutata su scala Likert a 7 punti, come precisato nella Sezione 10.1.1 del protocollo. |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| DA PROTOCOLLO "The end of study is defined as the last study visit (day 30 + 6 months) for the last subject". Questi 6 mesi dopo la LPLV sono necessari per un ultimo contatto con il paziente che potrebe essere anche solo telefonico. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 30 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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