E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure and preserved ejection fraction |
Insufficienza cardiaca e frazione di eiezione preservata |
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E.1.1.1 | Medical condition in easily understood language |
Heart failure and preserved ejection fraction |
Insufficienza cardiaca e frazione di eiezione preservata |
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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 | 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 |
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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 |
To evaluate the efficacy of vericiguat 10 mg in comparison to placebo on improving physical functioning from baseline to week 24.
To evaluate the efficacy of vericiguat 15 mg in comparison to placebo on improving physical functioning from baseline to week 24.
To evaluate the safety and tolerability of vericiguat.
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¿ Valutare l¿efficacia di vericiguat 10 mg rispetto al placebo sul miglioramento della funzionalit¿ fisica alla settimana 24 rispetto al basale. ¿ Valutare l¿efficacia di vericiguat 15 mg rispetto al placebo sul miglioramento della funzionalit¿ fisica alla settimana 24 rispetto al basale. ¿ Valutare la sicurezza e la tollerabilit¿ di vericiguat.
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of vericiguat 10 mg/ 15 mg in comparison to placebo on improving distance traveled on a 6-minute walk test (6MWT) from baseline to week 24 To evaluate the efficacy of vericiguat 10 mg/ 15 mg in comparison to placebo in increasing the proportion of patients with Kansas City Cardiomyopathy Questionnaire (KCCQ) physical limitation score (PLS) improvement from baseline by >5 points at 24 weeks and other thresholds (e.g. >3, >7, >10, >15, >20), and the proportions with these improvements in the other KCCQ domains; overall symptom score (OSS), clinical summary score (CSS), total symptom score (TSS) and symptom frequency score (SFS). To evaluate the efficacy of vericiguat 10 mg/ 15 mg in comparison to placebo in decreasing the proportion of patients with KCCQ PLS decline from baseline by >5 points at 24 weeks and the proportions with decline in the other KCCQ domains OSS, CSS, TSS and SFS. |
¿ Valutare l¿efficacia di vericiguat 10 mg e 15mg rispetto al placebo sul miglioramento della distanza percorsa nel test del cammino di 6 minuti (6MWT) alla settimana 24 rispetto al basale. ¿ Valutare l¿efficacia di vericiguat 10 mg rispetto al placebo nell¿aumentare la percentuale di pazienti che evidenziano un miglioramento rispetto al basale del punteggio relativo alla Limitazione Fisica (PLS) del Kansas City Cardiomyopathy Questionnaire (KCCQ) >5 punti a 24 settimane e altre soglie (ad esempio >3, >7, >10, >15, >20) e delle percentuali di pazienti che evidenziano questi miglioramenti negli altri domini del KCCQ: (OSS), (CSS), (TSS) e (SFS). ¿ Valutare l¿efficacia di vericiguat 15 mg rispetto al placebo nell¿aumentare la percentuale di pazienti che evidenziano un miglioramento rispetto al basale del punteggio PLS-KCCQ >5 punti a 24 settimane e altre soglie (ad esempio >3, >7, >10, >15, >20) e e nei domini KCCQ: OSS, CSS, TSS e SFS. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Previous diagnosis of chronic HF
- HF decompensation within 6 months prior to randomization, defined as hospitalization for HF or intravenous (IV) diuretic treatment for HF without hospitalization.
- N-terminal pro brain natriuretic peptide (NT-proBNP) =300 or brain natriuretic peptide (BNP) =100 pg/mL in sinus rhythm, or NT-proBNP =600 or BNP =200 pg/mL in atrial fibrillation within 30 days prior to randomization
- Diagnostic criteria of HFpEF by echocardiography assessed within 12 months prior to randomization (most recent measurement must be used to determine eligibility with no interim event signaling potential deterioration in ejection fraction)
- Left ventricular ejection fraction (LVEF) =45%
and
- Structural changes indicated by at least one of the following parameters:
¿ Left ventricle (LV) hypertrophy (any of the following: intraventricular septal or posterior wall thickness =1.1 cm, and/or LV mass index =115 g/m2 in male and =95 g/m2 in female),
or
¿ Left atrium (LA) enlargement (any of the following: left atrial volume (LAV) index =29 ml/m2, or LAV >58 mL in male and >52 mL in female patients, or LA area >20 cm2, or LA diameter >40 mm in male and >38 mm in female patients)
- NYHA class II or III at randomization
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In questo studio saranno arruolati pazienti di sesso maschile e femminile di età pari o superiore a 45 anni, affetti da HF cronica (classe NYHA II o III), con frazione di eiezione ventricolare sinistra preservata (LVEF =45%), livelli elevati dei peptidi natriuretici e pregressa HF scompensata.
Principali criteri di inclusione:
• Pregressa diagnosi di HF cronica • HF scompensata nei 6 mesi precedenti alla randomizzazione, definita come ricovero per HF o trattamento diuretico endovenoso (EV) per l’HF senza ricovero (trattamento ambulatoriale) • Frammento N-terminale del pro-peptide natriuretico cerebrale (NT-proBNP) =300 o peptide natriuretico cerebrale (BNP) =100 pg/ml se in ritmo sinusale oppure NT-proBNP =600 o BNP =200 pg/ml se in fibrillazione atriale nei 30 giorni precedenti alla randomizzazione • Criteri diagnostici di HFpEF ecocardiografici valutati nei 12 mesi precedenti alla randomizzazione (per determinare l’eleggibilità deve essere utilizzata la misurazione più recente, senza alcun evento intermedio che indichi un potenziale deterioramento della frazione di eiezione) o Frazione di eiezione ventricolare sinistra (LVEF) =45% e o Alterazioni strutturali indicate da almeno uno dei seguenti parametri: ¿ ipertrofia ventricolare sinistra (LV) (una qualsiasi delle seguenti condizioni: spessore della parete intraventricolare settale o posteriore =1,1 cm e/o indice di massa LV =115 g/m2 nell’uomo e =95 g/m2 nella donna) oppure ¿ ingrandimento atriale sinistro (LA) (una qualsiasi delle seguenti condizioni: indice del volume atriale sinistro (LAV) =29 ml/m2, o LAV >58 ml nell’uomo e >52 ml nella donna, o area LA >20 cm2 o diametro LA >40 mm nell’uomo e >38 mm nella donna) • Classe NYHA II o III alla randomizzazione
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E.4 | Principal exclusion criteria |
- Clinical instability at randomization, defined by
o Any IV treatment within 24h prior to randomization, and/or
o SBP =160 mmHg
o SBP <110 mmHg and/or DBP <40 mmHg and/or symptomatic hypotension
o Resting heart rate (HR) <50 or =100 beats per minute (bpm)
- Use of IV inotropes at any time between qualifying HF event and randomization
- Previous diagnosis of reduced ejection fraction (EF) (EF <40%)
- Hypertrophic obstructive cardiomyopathy, acute myocarditis, amyloidosis, sarcoidosis, or pericardial disease
- Primary valvular heart disease requiring surgery or intervention, or within 3 months after valvular surgery or intervention, or active endocarditis
- Acute coronary syndrome, including unstable angina, Non ST-elevation myocardial infarction or ST-elevation myocardial infarction, or Coronary artery bypass grafting (CABG) within 60 days prior to randomization, or indication for Percutaneous coronary intervention or CABG at the time of randomization
- Symptomatic carotid stenosis, or transient ischemic attack or stroke within 60 days prior to randomization
- Complex congenital heart disease
- Non-cardiac comorbidity (any of the following)
- Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 calculated by Modification of Diet in Renal Disease formula
o Hepatic insufficiency classified as Child-Pugh B or C
o Morbid obesity with a body mass index >45 kg/m2
o Malignancy or other non-cardiac condition limiting life expectancy to <1 year, per physician judgment
o Requires continuous home oxygen for severe pulmonary disease or has interstitial lung disease
o Patients with allergies, intolerance or hypersensitivity to investigational drug or any of the excipients
- Concurrent or anticipated use of nitrates or NO donors, phosphodiesterase type V (PDE5) inhibitors, or a Soluble guanylate cyclase (sGC) stimulator
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• Instabilità clinica alla randomizzazione, definita da o Qualsiasi trattamento EV nelle 24 ore precedenti alla randomizzazione e/o o Pressione arteriosa sistolica (SBP) =160 mmHg o Pressione arteriosa sistolica (SBP) <110 mmHg e/o pressione arteriosa diastolica (DBP) <40 mmHg e/o ipotensione sintomatica o Frequenza cardiaca (HR) a riposo <50 o =100 battiti al minuto (bpm) • Utilizzo di inotropi per via EV in qualsiasi momento tra l’evento qualificante di HF e la randomizzazione • Pregressa diagnosi di ridotta frazione di eiezione (EF) (EF <40%) • Cardiomiopatia ipertrofica ostruttiva, miocardite acuta, amiloidosi, sarcoidosi o pericardiopatia • Valvulopatia primaria che richieda un intervento chirurgico o una procedura, o nei 3 mesi successivi all’intervento chirurgico o alla procedura valvolare, oppure endocardite attiva • Sindrome coronarica acuta, inclusi angina instabile, infarto del miocardio senza sopraslivellamento ST o infarto del miocardio con sopraslivellamento ST, oppure bypass aorto-coronarico (CABG) nei 60 giorni precedenti alla randomizzazione o indicazione per un Intervento Coronarico Percutaneo o un CABG al momento della randomizzazione • Stenosi carotidea sintomatica o attacco ischemico transitorio oppure ictus nei 60 giorni precedenti alla randomizzazione • Cardiopatia congenita complessa • Comorbilità non cardiaca (una qualsiasi delle seguenti condizioni) o Velocità stimata di filtrazione glomerulare (eGFR) <30 ml/min/1,73 m2 calcolata applicando la formula Modification of Diet in Renal Disease o Insufficienza epatica classificata come Child Pugh B o C o Obesità patologica con un Indice di Massa Corporea >45 kg/m2 o Neoplasia o altra condizione non cardiaca che limiti l’aspettativa di vita a <1 anno, secondo la valutazione del medico o Pazienti che necessitano della somministrazione domiciliare continua di ossigeno per una patologia polmonare grave o affetti da pneumopatia interstiziale o Pazienti con allergie, intolleranza o ipersensibilità al farmaco sperimentale o a uno qualsiasi degli eccipienti • Utilizzo concomitante o previsto di nitrati o donatori di ossido nitrico (NO), inibitori della fosfodiesterasi di tipo V (PDE5) o di uno stimolatore della guanilato ciclasi solubile (sGC)
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E.5 End points |
E.5.1 | Primary end point(s) |
- Change in KCCQ PLS from baseline to week 24
- The incidence of treatment-emergent AEs |
- Change in KCCQ PLS from baseline to week 24 - The incidence of treatment-emergent AEs |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- From baseline to week 24
- From signing of informed consent to safety follow-up (at 28 weeks) |
- From baseline to week 24 - From signing of informed consent to safety follow-up (at 28 weeks) |
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E.5.2 | Secondary end point(s) |
Change in the 6 MWT from baseline to week 24 ; Change in the 6 MWT from baseline to week 24 |
Change in the 6 MWT from baseline to week 24; Change in the 6 MWT from baseline to week 24 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to week 24; From baseline to week 24 |
From baseline to week 24; From baseline to week 24 |
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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 | 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 | 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 | 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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 75 |
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 |
Canada |
Colombia |
Israel |
Japan |
Malaysia |
Russian Federation |
Serbia |
Singapore |
South Africa |
Taiwan |
United States |
Austria |
Belgium |
Bulgaria |
Germany |
Greece |
Hungary |
Italy |
Poland |
Portugal |
Spain |
Argentina |
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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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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |