E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pediatric heart failure 1 month to <18 years old |
insufficienza cardiaca pediatrica da 1 mese a <18 anni |
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E.1.1.1 | Medical condition in easily understood language |
Pediatric heart failure (HF) |
insufficienca cardiaca pediatrica |
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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 | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019279 |
E.1.2 | Term | 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 |
This study consist of two parts (Part 1 and Part 2).
Part 1: to evaluate the way the body absorbs, distributes and removes the drug LCZ696. This will help determine the proper dose of LCZ696 for Part 2 of the study.
Part 2: to compare the effectiveness and safety of LCZ696 with enalapril in pediatric heart failure patients over 52 weeks of treatment.
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• Parte 1: l’obiettivo primario è definire la farmacocinetica (PK) e la farmacodinamica (PD) di LCZ696 in pazienti pediatrici con insufficienza cardiaca
• Parte 2: l’obiettivo primario è determinare se LCZ696 è superiore a enalapril nel trattamento dei pazienti pediatrici con insufficienza cardiaca avvalendosi di un Global Rank endpoint
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Chronic heart failure resulting from left ventricular systolic dysfunction, and receiving chronic HF therapy (if not newly diagnosed)
- NYHA classification II-IV (older children: 6 to <18 years old) or Ross CHF classification II-IV (younger children: < 6 years old)
- Systemic left ventricular ejection fraction ≤ 40% or fractional shortening ≤20%
- For Part 1 PK/PD, patients must be treated with an ACEI (Angiotensin converting enzyme inhibitor) or ARB (Angiotensin receptor blockers) prior to screening. For Part 1 PK/PD, patients in Group 1 and 2 must be currently treated with the dose equivalent of at least enalapril 0.2 mg/kg prior to the LCZ696 3.1 mg/kg single dose assessment.
- Biventricular physiology with systemic left ventricle
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1. Il consenso informato scritto da parte del(i) genitore(i)/rappresentante(i) legale(i) deve essere ottenuto per i pazienti pediatrici prima di qualsiasi attività correlata allo studio. Il consenso o l’assenso può essere richiesto a seconda dell’età del paziente e delle leggi locali vigenti
2. Maschi o femmine, ospedalizzati o seguiti in ambulatorio, da 1 mese a < 18 anni di età
3. Diagnosi di insufficienza cardiaca cronica ascrivibile a una disfunzione sistolica del ventricolo sinistro, in terapia cronica per l’HF (a meno che il paziente non sia di nuova diagnosi)
4. Classificazione funzionale NYHA II-IV (pazienti da 6 a < 18 anni) e Ross CHF II-IV (pazienti da 1 mese a < 6 anni), in qualsiasi momento prima dello screening
5. Frazione di eiezione del ventricolo sinistro (LVEF) ≤ 40% o frazione di accorciamento ≤20% (valutata con l’ecocardiografia più recente, MRI, MUGA o angiografia del ventricolo sinistro 1 mese prima dello screening)
6. Fisiologia biventricolare con il ventricolo sinistro sistemico
7. Per la parte 1 PK / PD, i pazienti devono essere trattati con un ACE-inibitore (inibitore dell'enzima di conversione dell’angiotensina) o ARB (bloccanti del recettore dell'angiotensina) prima dello screening. Per la parte 1 PK / PD, i pazienti del Gruppo 1 e 2 devono essere trattati con la dose equivalente pari o superiore di enalapril 0,2 mg / kg (Tabella 3-1 del protocollo originale) prima dell’assunzione della dose singola di LCZ696 3.1 mg/kg; i pazienti del Gruppo 3 partecipano solo alla valutazione della dose di LCZ696 0,8 mg/kg e la dose di LCZ696 3,1 mg/kg per lo studio della farmacocinetica |
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E.4 | Principal exclusion criteria |
- Patient with single ventricle or systemic right ventricle
- Patients listed for heart transplantation (as United Network for Organ Sharing status 1A) or hospitalized waiting for transplant (while on inotropes or with ventricular assist device)
- Sustained or symptomatic dysrhythmias uncontrolled with drug or device therapy
- Patients that have had cardiovascular surgery or percutaneous intervention to palliate or correct congenital cardiovascular malformations within 3 months of the screening visit. Patients anticipated to undergo corrective heart surgery during the 12 months after entry into Part 2.
- Patients with unoperated obstructive or severe regurgitant valvular (aortic, pulmonary, or tricuspid) disease, or significant systemic ventricular outflow obstruction or aortic arch obstruction.
- Patients with restrictive or hypertrophic cardiomyopathy
- Active myocarditis
- Renal vascular hypertension (including renal artery stenosis)
- Moderate-to severe obstructive pulmonary disease
- Serum potassium >5.3 mmol/L at Visit 1 or at Visit 301
- History of angioedema
- Allergy or hypersensitivity to ACEI / ARB
Other protocol defined inclusion/exclusion criteria may apply. |
1. Pazienti con un singolo ventricolo o con il ventricolo destro sistemico
2. Pazienti che al momento dell’arruolamento sono in lista trapianto con lo status UNOS (United Network for Organ Sharing) 1A oppure ospedalizzati in attesa di trapianto in terapia inotropa oppure con assistenza ventricolare meccanica.
3. Aritmie sostenute e sintomatiche non controllate con terapia farmacologica o dispositivo
4. Pazienti sottoposti, nei 3 mesi precedenti alla visita di screening, ad un intervento di chirurgica cardiovascolare o intervento correttivo percutaneo per malattia congenita cardiaca/cardiovascolare; pazienti per i quali è previsto un intervento chirurgico cardiaco nei 12 mesi successivi l’ingresso nella parte 2
5. Pazienti con stenosi valvolare o rigurgito severo valvolare non corretto (aortica, polmonare o tricupside), oppure ostruzione significativa del tratto di efflusso del ventricolo sinistro o dell’arco aortico
6. Pazienti con cardiomiopatia restrittiva o ipertrofica
7. Miocardite attiva (con diagnosi di presunta o attiva miocardite entro i 3 mesi dall’arruolamento)
8. Ipotensione sintomatica o pressione arteriosa sistolica (SBP) al di sotto del 5° percentile per età, alla visita di screening e come descritto dall’appendice 4 del protocollo
9. Ipertensione nefrovascolare (inclusa la stenosi dell’arteria renale)
10. Iptertensione polmonare severa (definita dall’indice resistenza vascolare polmonare (PVR) >6 Wood units-m2) refrattaria agli agenti vasodilatatori (come ossigeno, nitroprussiato, o ossido nitrico). La misurazione del PVR non è richiesta dallo studio per la determinazione dell’eleggibilità.
11. Anamnesi pregressa o attuale evidenza clinica di pneumopatia ostruttiva severa o malattia reattiva delle vie respiratorie (e.g. asma)
12. Potassio sierico >5.3 mmol/L, alla Visita 1 o alla Visita 301
13. Pazienti con significativa disfunzione renale (eGFR < 30% calcolato usando la formula di Schwartz modificata per età e statura); epatica (aspartato aminotransferasi o alanina aminotransferasi > 3 i limiti superiori di normalità); gastrointestinale o disordine biliare (che possa compromettere l’assorbimento, metabolismo, o escrezione dei farmaci somministrati per via orale)
14. Stadio terminale, malattie severe (e.g. leucemia linfocitica acuta) o alterazioni dei valori di laboratorio significativi che, ad opinione del medico, precludono la partecipazione allo studio o la sopravvivenza
15. Anamnesi positiva per angioedema
16. Pazienti con allergie o ipersensibilità agli ACEi/ARB
Per ulteriori informazioni consultare la sezione 4.2 del protocollo |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1:
- Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Maximum drug concentration in plasma (Cmax). Cmax will be determined for LCZ696 analytes (sacubitril, LBQ657, and valsartan) by using non-compartmental methods.
- Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Time to maximum plasma concentration (Tmax). Tmax will be determined for LCZ696 analytes (sacubitril, LBQ657, and valsartan) by using non-compartmental methods.
- Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): area under the plasma concentration-time curve from time zero to infinity (AUCinf) and area under the plasma concentration-time curve from time zero to last (AUClast). AUCinf and AUClast will be determined for LCZ696 analytes (sacubitril, LBQ657, and valsartan) by using non-compartmental methods.
- Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Clearance from plasma (CL/F). CL/F will be determined for LCZ696 analytes (sacubitril, LBQ657, and valsartan) by using non-compartmental methods.
- Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Time required to drug concentration to decrease by half (T 1/2). T 1/2 will be determined for LCZ696 analytes (sacubitril, LBQ657, and valsartan) by using non-compartmental methods
- Pharmacodynamics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Plasma B-type natriuretic peptide (BNP), plasma N-terminal pro-brain natriuretic peptide (NTproBNP). The 24 hour post dose is optional depending on blood volume restrictions.
- Pharmacodynamics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Plasma cyclic guanosine monophosphate (cGMP). The 24 hour post dose is optional depending on blood volume restrictions.
- Pharmacodynamics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Urine cGMP. The urine samples will be collected at pre-dose and once between 4 to 8 hours post dosing.
Part 2:
- Percentage of patients falling into each category based on global ranking. The global ranking is based on clinical events such as death, listing for urgent heart transplant, mechanical life support requirement at end of study, worsening heart failure (HF), New York Heart Association (NYHA)/Ross, Patient Global Impression of Severity (PGIS), Pediatric Quality of Life Inventory (PedsQL) physical functioning domain. The primary endpoint will be derived based on 5 categories ranking worst to best outcome. |
Parte 1: Farmacocinetica (PK) e la farmacodinamica (PD) di LCZ696 in pazienti pediatrici con insufficienza cardiaca
Parte 2: l’obiettivo primario è determinare se LCZ696 è superiore a enalapril nel trattamento dei pazienti pediatrici con insufficienza cardiaca avvalendosi di un Global Rank endpoint
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1:
Phramacokinetics: Time Frame: 0, 0.5, 1, 2, 4, 8, 10, and optional 24 hours post dosing.
Pharmacodynamics:
- of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Plasma Nterminal pro-brain natriuretic peptide (NTproBNP):
Time Frame: 0 and optional 24 hours post dosing.
The 24 hour post dose is optional depending on blood volume restrictions.
- of LCZ696 analytes: Plasma plasma B-type natriuretic peptide (BNP):
Time Frame: 0, 4, 8 hour post dosing.
- of LCZ696 analytes: Plasma cyclic guanosine monophosphate (cGMP):
Time Frame: 0, 4, 8 hour post dosing.
- of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Urine cGMP:
Time Frame: 0, Between 4 and 8 hours post dose.
An urine sample will be collected at pre-dose and between 4 to 8 hours
Part 2: Up to 52 weeks |
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E.5.2 | Secondary end point(s) |
Parti 1: To assess the safety and tolerability of LCZ696 in pediatric patients with heart failure
Part 2:
- Time to first occurrence of Category 1 or Category 2 event. Category 1: Death; United Network for Organ Sharing (UNOS) status 1A listing for heart transplant or equivalent; VAD/ECMO/mechanical ventilation/intra-aortic balloon pump requirement for life support at end of study. Category 2: Worsening HF (WHF); defined by signs and symptoms of WHF that requires an intensification of HF therapy
- Change from baseline in NYHA/Ross functional class. NYHA/Ross functional class will be compared through 52 weeks of double-blind treatment
- Change from baseline in Patient Global impression of severity score (PGIS) scale.
PGIS scale will be compared for LCZ696 and enalapril through 52 weeks of double-blind treatment
- Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Clearance from plasma in steady state (CL,ss). The steady state population PK parameter clearance will be estimated to be used in model.
- Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Volume of distribution in steady state. The steady state population PK parameter volume of distribution will be estimated to be used in model.
- Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Absorption rate constant in steady state (Ka,ss). The steady state population PK parameter Ka will be estimated to be used in model.
- Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Time required to drug concentration to decrease by half in steady state (T 1/2,ss). The steady state population PK parameter T 1/2 will be estimated to be used in model.
- Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Maximum drug concentration in plasma at steady state (Cmax,ss). The steady state population PK parameter Cmax will be estimated to be used in model.
- Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Lowest plasma concentration observed during a dosing interval at steady state (Cmin,ss). The steady state population PK parameter Cmin will be estimated to be used in model.
- Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady state (AUCtau,ss). The steady state population PK parameter AUC will be estimated to be used in model. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Time to first occurrence of Cat 1 or Cat 2 event: 52 weeks.
- Change from baseline in NYHA/Ross functional class: Baseline to 52 weeks.
- Change from baseline in (PGIS) scale: Baseline to 52 weeks.
- Population PK of LCZ696 analytes: Clearance from plasma in steady state (CL,ss), Volume of distribution in steady state, Absorption rate constant in steady state (Ka,ss), Time required to drug concentration to decrease by half in steady state (T 1/2,ss), Maximum drug concentration in plasma at steady state (Cmax,ss), Lowest plasma concentration observed during a dosing interval at steady state (Cmin,ss), area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady state (AUCtau,ss): Week 2, 12, 52. |
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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 | 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) | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 46 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
China |
Croatia |
Czech Republic |
Egypt |
Finland |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Lebanon |
Malaysia |
Netherlands |
Norway |
Philippines |
Poland |
Russian Federation |
Saudi Arabia |
Singapore |
Slovakia |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
United Arab Emirates |
United Kingdom |
United States |
Jordan |
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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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A patient will be considered to have completed the study when the patient has completed the last visit planned in the protocol.
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LVLS |
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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 | 6 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |