E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Heart Failure With Reduced Ejection Fraction |
Insufficienza Cardiaca Cronica Con Ridotta Frazione Di Eiezione |
|
E.1.1.1 | Medical condition in easily understood language |
Chronic Heart Failure |
Malattia Cronica Cardiovascolare |
|
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 | LLT |
E.1.2 | Classification code | 10008908 |
E.1.2 | Term | Chronic heart failure |
E.1.2 | System Organ Class | 100000004849 |
|
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 |
To evaluate the effect of treatment with omecamtiv mecarbil compared with placebo on the time to cardiovascular (CV) death or first HF event, whichever occurs first, in subjects with chronic HF with reduced ejection fraction (HFrEF) receiving standard of care (SoC) therapy.
An HF event is defined as presentation of the patient for an urgent, unscheduled clinic/office/ED visit, or hospital admission, with a primary diagnosis of HF, where the patient exhibits new or worsening symptoms of HF on presentation, has objective evidence of new or worsening HF, and receives initiation or intensification of treatment specifically for HF (Hicks et al, 2015). Changes to oral diuretic therapy do not qualify as initiation or intensification of treatment. |
Valutazione degli effetti del trattamento con omecamtiv mecarbil (OM) rispetto al placebo fino alla morte per causa cardiovascolare (CV) o al primo evento di insufficienza cardiaca, in base all’evento che si verifica per primo, nei soggetti affetti da insufficienza cardiaca cronica con frazione di eiezione ridotta (ICFEr) che seguono una terapia standard. Si parla di evento di insufficienza cardiaca quando un paziente richiede una visita urgente e non programmata al pronto soccorso/in ambulatorio/in clinica o viene ricoverato in ospedale con una diagnosi primaria di insufficienza cardiaca e presenta un peggioramento o la comparsa di nuovi sintomi di insufficienza cardiaca, un’evidenza obiettiva di una nuova insorgenza o un aggravamento di insufficienza cardiaca e viene iniziato o intensificato il trattamento specifico per questa condizione (Hicks et al, 2015). Le modifiche apportate alla terapia diuretica orale non costituiscono un avvio né un’intensificazione del trattamento.
|
|
E.2.2 | Secondary objectives of the trial |
To evaluate the effects of OM on time to: - CV death - HF hospitalization - all-cause death
To evaluate the effects of treatment with OM on change in patient-reported outcomes (PROs). |
Valutazione degli effetti di OM fino a: – Morte per causa CV - Ospedalizzazione per insufficienza cardiaca - Decesso per tutte le cause ¿ Valutazione degli effetti del trattamento con OM sulla variazione degli esiti riferiti dai pazienti (PRO, Patient-Reported Outcome). |
|
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 |
Pharmacogenetics Version: 1.0 Date: 31/08/2016 Title: Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy and Safety of Omecamtiv Mecarbil on Mortality and Morbidity in Subjects With Chronic Heart Failure With Reduced Ejection Fraction (Substudy present in section 7.4) Objectives: These optional pharmacogenetic analyses focus on inherited genetic variations to evaluate their possible correlation to the disease and/or responsiveness to the therapies used in this study. The goals of the optional studies include the use of genetic markers to help in the investigation of OMand/or to identify subjects who may have positive or negative response to OM
|
Farmacogenetica Versione: 1.0 Data: 31/08/2016 Titolo: Studio multicentrico, randomizzato, in doppio cieco, controllato con placebo volto a
valutare l’efficacia e la sicurezza di omecamtiv mecarbil in termini di morbilità e mortalità nei
soggetti affetti da insufficienza cardiaca cronica con frazione di eiezione ridotta (sottostudio presente nella sezione 7.4) Obiettivi: analizzare le variazioni genetiche ereditate per valutare la loro eventuale correlazione con la malattia e/o la risposta alle terapie usate in questo studio. Gli obiettivi degli studi opzionali includono l'uso di marcatori genetici per aiutare nelle indagini di OM e/o per identificare i soggetti che possono avere risposta positiva o negativa per OM
|
|
E.3 | Principal inclusion criteria |
Subject has provided informed consent
Male or female, = 18 to = 85 years of age
History of chronic HF
LVEF = 35%
NYHA class II to IV
Managed with HF SoC therapies consistent with regional clinical practice guidelines
Current hospitalization with primary reason of HF or prior HF hospitalization, or urgent HF admission to emergency department (ED) within 1 year prior to screening
BNP level = 125 pg/mL or an NT-proBNP level = 400 pg/mL at most recent screening assessment (for subjects with atrial fibrillation, the cut off levels are: BNP = 375 pg/mL or NT proBNP = 1200 pg/mL)
|
Il soggetto ha fornito il consenso informato
Maschi o femmine, con età = 18 anni = 85 anni
Anamnesi di insufficienza cardiaca cronica
LVEF = 35%
NYHA dalla classe II alla IV
Trattamento dell'insufficienza cardiaca con terapie standard compatibili con le linee guida di buona pratica clinica regionali
Ospedalizzazione per insufficienza cardiaca o prima ospedalizzazione per insufficienza cardiaca, o insufficienza cardiaca urgente con ammissione al dipartimento di emergenza (ED) entro un anno prima dello screening
Livelli di BNP = 125 pg/mL o un livello di NT-proBNP = 400 pg/mL rispetto alla valutazione di screenig più recente (per i soggetti con fibrillazione atriale, l'intervallo dei livelli è: BNP = 375 pg/mL o NT proBNP = 1200 pg/mL.
|
|
E.4 | Principal exclusion criteria |
Inability to swallow study medication tablet
Receiving mechanical hemodynamic support or mechanical ventilation = 7 days prior to randomization
Receiving IV inotropes or IV vasopressors = 3 days prior to randomization
Receiving IV diuretics or IV vasodilators, or supplemental oxygen therapy = 12 hours prior to randomization
Acute coronary syndrome, stroke, or transient ischemic attack, major cardiac surgery, percutaneous coronary intervention, or valvuloplasty within the 3 months prior to randomization
Severe uncorrected valvular heart disease, or hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease
Routinely scheduled outpatient intravenous infusions for HF (eg, inotropes, vasodilators, diuretics) or routinely scheduled ultrafiltration
Systolic blood pressure > 140 mmHg or < 85 mmHg, or diastolic blood pressure > 90 mmHg, or heart rate > 110 beats per minute, or < 50 beats per minute at screening
Estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2
|
Incapacità di deglutire la compressa in studio
Ricevere supporto emodinamico o ventilazione meccanica in un tempo = 7 giorni prima della randomizzazione
Assumere inotropi IV o vasopressori IV in un tempo = 3 giorni prima della randomizzazione
Ricevere diuretici IV o vasodilatatori IV o terapia di ossigeno supplementare in un tempo = a 12 ore prima della randomizzazione
Sindrome coronarica acuta, ictus, o attacco ischemico transitorio,chirurgia cardiaca maggiore, intervento coronarico percutaneo, o valvuloplastica entro i 3 mesi precedenti la randomizzazione
Gravi malattie cardiache valvolari non corrette, o cardiomiopatia ipertrofica ostruttiva, miocardite attiva, pericardite costrittiva, o malattia cardiaca congenita clinicamente significativa
Infusioni intravenose ambulatoriali programmate per insufficienza cardiaca (eg, inotropi, vasodilatatori, diuretici) o ultrafiltrazione di routine programmata
Pressione sistolica > 140 mmHg o < 85 mmHg, o pressione diastolica > 90 mmHg, o frequenza cardiaca > 110 battiti al minuto, o < 50 battiti al minuto allo screening
Velocità di filtrazione glomerulare stimata (eGFR) < 20 mL/min/1.73m2
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Composite of time to CV death or first HF event, whichever occurs first |
Composita di tempo alla morte cardiovascolare o primo evento di insufficienza cardiaca, a seconda di quale si verifica per primo |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Duration of trial |
Durata dello studio |
|
E.5.2 | Secondary end point(s) |
Time to CV death. Change in Kansas City Cardiomyopathy Questionnaire Total Symptoms Score (KCCQ TSS) from baseline to week 24. Time to first HF hospitalization. Time to all-cause death. |
Tempo alla morte cardiovascolare. Cambiamenti nel Kansas City Cardiomyopathy Questionnaire Total Symptoms Score (KCCQ TESS) dal basale alla settimana 24. Tempo alla prima ospedalizzazione per insufficienza cardiaca. Tempo a tutte le cause di morte. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Duration of trial |
Durata dello studio |
|
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 | 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 | Yes |
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 | Yes |
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
| 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 | 26 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 318 |
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 | Information not present in EudraCT |
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 |
Brazil |
Canada |
Chile |
China |
Colombia |
Japan |
Mexico |
New Zealand |
Russian Federation |
South Africa |
Turkey |
Ukraine |
United States |
Austria |
Belgium |
Bulgaria |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Netherlands |
Poland |
Portugal |
Romania |
Slovakia |
Spain |
Sweden |
Switzerland |
United Kingdom |
Czechia |
Argentina |
|
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
|
The end of study is when the last subject has completed the end of study assessments. |
Lo studio termina quando l'ultimo soggetto ha completato le valutazioni dello studio. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |