| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Heart Failure and Left Ventricular Systolic Dysfunction |
Insufficienza cardiaca cronica e disfunzione sistolica ventricolare sinistra
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| E.1.1.1 | Medical condition in easily understood language |
| Chronic Heart Failure |
| Insufficienza cardiaca cronica |
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| 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 | 15.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063083 |
| E.1.2 | Term | Chronic left ventricular failure |
| E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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| 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 |
(i) to select an oral modified release (MR) formulation and dose of omecamtiv mecarbil for chronic twice daily (BID) dosing in
subjects with HF and left ventricular systolic dysfunction and (ii) to characterize its pharmacokinetics (PK) after 12 weeks of treatment. |
| Gli obiettivi primari di questo studio sono: (i) scegliere una formulazione orale a rilascio modificato (MR) e una dose di omecamtiv mecarbil da destinare alla somministrazione cronica bigiornaliera (BID) in soggetti con insufficienza cardiaca e disfunzione sistolica ventricolare sinistra e (ii) descriverne la farmacocinetica (FC) dopo 12 settimane di trattamento. |
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| E.2.2 | Secondary objectives of the trial |
to evaluate the safety and tolerability of oral omecamtiv mecarbil
to measure changes in systolic ejection time (SET), stroke volume, left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), and heart rate after 12 weeks of oral dosing with omecamtiv mecarbil
to evaluate the effect of 12 weeks of oral dosing with omecamtiv mecarbil on N-terminal pro–B-type natriuretic peptide (NT-proBNP)
to evaluate the PK of omecamtiv mecarbil metabolites with oral omecamtiv mecarbil dosing |
• valutare sicurezza e tollerabilità di omecamtiv mecarbil orale
• misurare le variazioni del tempo di eiezione sistolica (SET), gittata sistolica, diametro ventricolare sinistro tele-sistolico (LVESD), diametro ventricolare sinistro tele-diastolico (LVEDD) e frequenza cardiaca dopo 12 settimane di somministrazione di omecamtiv mecarbil orale
• valutare l'effetto di 12 settimane di somministrazione orale di omecamtiv mecarbil sulla frazione plasmatica N-terminale del precursore peptidico natriuretico celebrare (NT-proBNP)
• valutare la farmacogenetica (FC) dei metaboliti di omecamtiv mecarbil con la somministrazione orale di omecamtiv mecarbil
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Dose Escalation Cohorts:
4.1.1 Subject has provided informed consent.
4.1.2 Male or female ≥ 18 years and ≤ 85 years of age at the time of informed consent.
4.1.3 History of chronic HF, defined as requiring treatment for HF for a minimum of 4 weeks prior to screening.
4.1.4 Treated for HF with stable, optimal pharmacological therapy. In general, optimal treatment will include a beta-blocker and an ACE inhibitor and/or an angiotensin receptor blocker at doses shown to be efficacious in HF trials, unless not tolerated. Stable medical therapy is defined as having no new HF drug class introduced or uptitrated ≥ 4 weeks prior to randomization.
4.1.5 LVEF ≤ 40% (echocardiogram, radionuclide ventriculography, cardiac magnetic resonance imaging, or contrast ventriculography) within 18 months prior to randomization and without an intervening value of > 40%.
4.1.6 NT-proBNP ≥ 200 pg/mL (≥ 1200 pg/mL if the subject has atrial fibrillation at presentation) at screening; (Note: enrollment of subjects with atrial fibrillation will be limited to up to approximately 20% of planned enrollment in each cohort).
Expansion Phase:
4.1.7 Subject has provided informed consent.
4.1.8 Male or female ≥ 18 years and ≤ 85 years of age at the time of informed consent.
4.1.9 History of chronic HF, defined as requiring treatment for HF for a minimum of 4 weeks prior to screening.
4.1.10 Treated for HF with stable, optimal pharmacological therapy. In general, optimal treatment will include a beta-blocker and an ACE inhibitor and/or an angiotensin receptor blocker at doses shown to be efficacious in HF trials, unless not tolerated. Stable medical therapy is defined as having no new HF drug class introduced or uptitrated ≥ 4 weeks prior to randomization.
4.1.11 NYHA class II or III symptoms.
4.1.12 LVEF ≤ 40% by centrally read screening echocardiogram.
4.1.13 Acceptable echocardiographic image quality of screening echocardiogram per central echo core laboratory
4.1.14 NT-proBNP ≥ 200 pg/mL (≥ 1200 pg/mL if the subject has atrial fibrillation at presentation) at screening; (Note: enrollment of subjects with atrial fibrillation will be limited to up to approximately 20% of planned cohort enrollment). |
| Sono considerati eleggibili per questo studio soggetti di entrambi i sessi di età ≥18 e ≤85 anni. Per essere arruolati i soggetti devono essere stati trattati per un periodo ≥4 settimane con una terapia farmacologica ottimale stabile che comprenda un beta bloccante e un inibitore dell'enzima di conversione dell'angiotensina o un bloccante del recettore dell'angiotensina, tranne nei casi di intolleranza. I soggetti arruolati nella fase di intensificazione della dose devono avere uno storico di frazione di eiezione ventricolare sinistra (LVEF) (entro 18 mesi) ≤ 40% (ecocardiogramma, ventricolografia a radionuclidi, risonanza magnetica cardiaca o ventricolografia con contrasto) senza un valore intermedio > 40%. I soggetti arruolati nella fase di espansione devono avere un ecocardiogramma allo screening con un’immagine qualitativamente accettabile e il valore di LVEF deve essere ≤ 40% determinato dalla valutazione centralizzata dell’ecocardiogramma di screening. Il valore di NT-proBNP deve essere ≥ 200 pg/mL (≥1200 pg/mL nel caso il quadro clinico iniziale del soggetto presenti fibrillazione atriale). La percentuale di soggetti con fibrillazione atriale arruolati non può superare il 20% per ciascuna coorte. I soggetti arruolati in una qualsiasi delle coorti di intensificazione della dose devono essere disponibili a sottoporsi a numerosi prelievi per le analisi FC, per esempio nelle prime 12 ore dopo la prima e l'ultima dose di omecamtiv mecarbil. I soggetti arruolati nella fase di espansione devono presentare un'insufficienza cardiaca di classe II o III della New York Heart Association (NYHA ). |
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| E.4 | Principal exclusion criteria |
Dose Escalation Cohorts and Expansion Phase:
4.2.1 Cardiac resynchronization therapy (CRT) or ICD implantation within 30 days prior to enrollment.
4.2.2 NYHA class IV.
4.2.3 Hospitalization for any reason within 30 days prior to randomization.
4.2.4 Likely to receive within 3 months after randomization, in the opinion of the Investigator, planned revascularization, implantation of ICD or CRT, ventricular assist device, continuous or intermittent inotropic therapy, hospice care, or cardiac transplant.
4.2.5 Severe uncorrected valvular heart disease.
4.2.6 Hypertrophic obstructive cardiomyopathy, active myocarditis, or constrictive pericarditis, or clinically significant congenital heart disease.
4.2.7 Unstable angina or persistent angina at rest within 30 days prior to randomization .
4.2.8 Chronic antiarrhythmic therapy, with the exception of amiodarone.
4.2.9 Routinely scheduled outpatient IV infusions for HF (eg, inotropes, vasodilators [eg, nesiritide], diuretics) or routinely scheduled ultrafiltration.
4.2.10 Systolic BP > 160 mm Hg or < 90 mm Hg, or diastolic BP > 90 mm Hg, or HR > 110 beats per minute (bpm) or HR < 50 bpm at screening.
4.2.11 Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at screening.
4.2.12 Currently taking, or has taken within 14 days prior to randomization, a potent CYP3A4 inhibitor.
4.2.13 Currently taking, or has taken within 28 days prior to randomization, a potent CYP3A4 inducer.
4.2.14 Severe, concomitant noncardiovascular disease that is expected to reduce life expectancy to less than 1 year.
4.2.15 Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal) or receiving renal replacement therapy by dialysis.
4.2.16 Malignancy within 5 years prior to randomization with the following exceptions: localized basal or squamous cell carcinoma of the skin or cervical intraepithelial neoplasia.
4.2.17 Untreated hypothyroidism or hyperthyroidism, adrenal insufficiency, active vasculitis due to collagen vascular disease.
4.2.18 Hepatic impairment
4.2.19 Any acute or serious co-morbid condition (eg, major infection or hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction) that, in the judgment of the investigator, could lead to premature termination of study participation or interfere with the measurement of, or the interpretation of, the efficacy and safety assessments in the study
4.2.20 Previously received omecamtiv mecarbil.
4.2.21 Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study.
4.2.22 Recent (within 3 months) history of alcohol or illicit drug abuse based on self-report.
4.2.23 Known sensitivity to any of the products to be administered during dosing.
4.2.24 Female subject of childbearing potential who is not willing to inform her partner of her participation in this clinical study and use at least 1 highly effective method of birth control during treatment and for an additional 5 days after the last dose of IP or male subject with a female partner of childbearing potential who does not agree to inform his partner of his participation in this clinical study and, during treatment and for 5 days after the last dose of IP, to abstain from sexual intercourse or use at least 1 highly effective method of birth control or male subject with a
pregnant partner who does not agree to sexual abstinence or using a condom during the study and for an additional 5 days after the last dose;
4.2.25 Female subject is pregnant or breastfeeding or is planning to become pregnant during treatment or within 5 days after the end of treatment.
(Full list in protocol) |
I principali criteri di esclusione sono i seguenti: impianto di resincronizzazione cardiaca (CRT) o defibrillatore cardioverter impiantabile (ICD), o ricovero per qualsiasi ragione nei 30 giorni precedenti la randomizzazione; soggetti in cui nei 3 mesi successivi alla randomizzazione, secondo il parere dello sperimentatore, sia probabile l'impianto di un ICD o CRT, di un dispositivo di assistenza ventricolare, una terapia inotropa continua o intermittente, il ricovero in luoghi di lungodegenza, o il trapianto cardiaco; severa cardiopatia valvolare non controllata; cardiomiopatia ostruttiva ipertrofica, miocardite attiva o pericardite costrittiva, o cardiopatia congenita clinicamente significativa; angina instabile o angina persistente a riposo; terapia cronica con antiaritmici (tranne con amiodarone), o infusioni EV ambulatoriali programmate per la cura dell'insufficienza cardiaca (per es. con sostanze inotrope, vasodilatatori [per es., nesiritide], diuretici) o ultrafiltrazione programmata di routine; pressione arteriosa sistolica (BP) > 160 mm Hg o < 90 mm Hg o diastolica > 90 mm Hg, o frequenza cardiaca > 110 battiti al minuto(bpm) o < 50 bpm; stima di filtrazione glomerulare (eGFR) < 30 mL/min/1,73 m2 al momento dello screening; paziente sottoposto a trapianto a carico di organo maggiore o in dialisi; bilirubina totale (TBL) ≥ 2 volte il limite superiore della norma (ULN), o alanina aminotransferasi (ALT) o aspartato aminotransferasi (AST) ≥ 3 volte il limite superiore della norma (ULN) al momento dello screening. Sono esclusi i soggetti che abbiano assunto un potente inibitore del CYP3A4 nei 14 giorni precedenti l'arruolamento o un potente induttore del CYP3A4 nei 28 giorni precedenti l'arruolamento (per i dettagli sui farmaci vedere capitolo esclusioni 4.2.12.e 4.2.13) . Sono esclusi inoltre i soggetti che presentano una condizione di comorbidità acuta o grave (come infezione maggiore o disfunzione ematologica, renale, metabolica, gastrointestinale o endocrina) che possa interferire con lo studio. I soggetti non devono aver assunto omecamtiv mecarbil prima della partecipazione allo studio.
I soggetti di sesso femminile non devono essere in gravidanza o allattamento. Le donne in premenopausa devono essere disposte ad adottare almeno un metodo contraccettivo di elevata efficacia durante il trattamento e per almeno 5 giorni dopo la fine del trattamento. I soggetti di sesso maschile con partner in età fertile devono astenersi dai rapporti sessuali o utilizzare metodi contraccettivi altamente efficaci durante lo studio e per almeno 5 giorni successivi l'ultima dose di prodotto sperimentale (PS) e, in caso tali partner siano in gravidanza o lo diventino, i soggetti devono astenersi dai rapporti sessuali o fare uso di preservativo durante lo studio e per almeno 5 gironi dopo l’ultima dose di farmaco sperimentale.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose Escalation Phase:
Cmax, time at which Cmax is attained (Tmax), Cmin and AUC12h of omecamtiv mecarbil
Expansion Phase:
Cmax and concentration prior to investigational product administration (Cpredose) of omecamtiv mecarbil |
Fase di intensificazione della dose
• Concentrazione massima osservata(Cmax), tempo in cui viene raggiunta la Cmax (Tmax), concentrazione minima osservata (Cmin) e area sottesa alla curva rilevata il giorno 7, 12 ore dopo la somministrazione del prodotto sperimentale omecamtiv mecarbil (AUC12h)
Fase di espansione
• Cmax e concentrazione precedente la somministrazione (Cpre-somministrazione) di omecamtiv mecarbil alle settimane 1, 4, 8 e 12 della somministrazione orale cronica bigiornaliera
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Dose Escalation Phase:
following dose on day 7
Expansion Phase:
at weeks 1, 4, 8, and 12 following chronic oral BID dosing |
fase di Dose Escalation :
dopo la dose al giorno 7
Fase di espansione:
alle settimane 1, 4, 8, e 12 dopo somministrazione orale cronica BID
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| E.5.2 | Secondary end point(s) |
Expansion phase only:
changes from baseline in SET, stroke volume, LVESD, LVEDD, and HR
change from baseline in NT-proBNP |
• Variazioni rispetto al basale dei valori di SET, gittata cardiaca, diametro ventricolare sinistro tele-sistolico (LVESD), diametro ventricolare sinistro tele-diastolico (LVEDD) e frequenza cardiaca rilevati alla settimana 12
• Alla settimana 12 variazione rispetto al basale dell’ NT-proBNP
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Lo studio ha due fasi: una di dose escalation e una di espansione di arruolamento |
| Trial has two phases: a dose escalation phase and an enrollment expansion phase |
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| 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 | 4 |
| 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 | 57 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Lithuania |
| Netherlands |
| Poland |
| United Kingdom |
| United States |
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| 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
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LPLV (= primary completion date).
Including the time of the last contact of a study subject to obtain vital status information, the end of trial will be approximately 3 months following the primary completion date (i.e. 3 months following LPLV). |
LPLV ( data di completamebnto primaria).
Include l'ultimo contatto del soggetto per valutare il suo vital status, la fine dello studio avverrà all'incirca 3 mesi dopo la LPLV |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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