Source: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-004207-22/IT
Timestamp: 2018-11-18 13:57:03+00:00
Document Index: 104452712

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EudraCT Number: 2015-004207-22
Sponsor's Protocol Code Number: CLCZ696B2319
Date on which this record was first entered in the EudraCT database: 2017-01-26
A.2 EudraCT number 2015-004207-22
Multicenter, open-label, study to evaluate safety, tolerability, pharmacokinetics and, pharmacodynamics of LCZ696 followed by a 52-week randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared with enalapril in pediatric patients from1 month to < 18 years of age with heart failure due to systemic left ventricle systolic dysfunction
Studio multicentrico, in aperto, con somministrazione
singola, per valutare la sicurezza, la tollerabilità, la
farmacocinetica e la farmacodinamica di LCZ696 seguito
dallo studio di 52 settimane, randomizzato, in doppio cieco,
a gruppi paralleli, con controllo attivo per valutare
l’efficacia e la sicurezza di LCZ696 rispetto ad enalapril in
pazienti pediatrici di età compresa tra 1 mese e < 18 anni
con insufficienza cardiaca dovuta a disfunzione sistolica
del ventricolo sinistro sistemico
Pharmacokinetics, pharmacodynamics, safety and efficacy study of LCZ696 in children (1 month to < 18 years) with heart failure
Farmacocinetica , farmacodinamica, sicurezza ed efficacia di LCZ696 in
bambini di età compresa (1 mese e < 18 anni)
A.4.1 Sponsor's protocol code number CLCZ696B2319
A.8 EMA Decision number of Paediatric Investigation Plan P/240/2015
B.4.1 Name of organisation providing support Novartis Pharma Service AG
B.5.1 Name of organisation Novartis Farma
B.5.3.1 Street Address Largo Umberto Boccioni 1
B.5.3.2 Town/ city Origgio (VA)
B.5.3.3 Post code 21040
B.5.4 Telephone number 003996541
B.5.6 E-mail info.studiclinici@novartis.com
D.3.1 Product name LCZ696 12.5 mg film-coated granules in capsule (4 x 3.125 mg film-coated granules)
D.3.2 Product code LCZ696
D.3.4 Pharmaceutical form Granules
D.3.8 INN - Proposed INN sacubitril/valsartan
D.3.9.3 Other descriptive name SACUBITRIL VALSARTAN
D.3.9.4 EV Substance Code SUB171905
D.2.1.1.1 Trade name Entresto
D.3.1 Product name LCZ696 50 mg
D.3.1 Product name LCZ696 100 mg
D.3.1 Product name LCZ696 200 mg
D.2.1.1.1 Trade name Enalapril
D.2.1.1.2 Name of the Marketing Authorisation holder Lek Pharmaceuticals d.d.
D.3.1 Product name Enalapril 2.5 mg
D.3.8 INN - Proposed INN enalapril
D.3.9.3 Other descriptive name ENALAPRIL MALEATE
D.3.9.4 EV Substance Code SUB01884MIG
D.3.1 Product name Enalapril 5 mg
D.3.1 Product name Enalapril 10 mg
D.3.1 Product name LCZ696 31.25 mg film-coated granules in capsule (10 x 3.125 mg film-coated granules)
D.3.10.3 Concentration number 31.25
D.8.3 Pharmaceutical form of the placebo Granules
D.8 Placebo: 7
D.8 Placebo: 8
Pediatric heart failure 1 month to <18 years old
insufficienza cardiaca pediatrica da 1 mese a <18 anni
insufficienca cardiaca pediatrica
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.
•	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
- 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
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
- 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
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
- 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.
- 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
Phramacokinetics: Time Frame: 0, 0.5, 1, 2, 4, 8, 10, and optional 24 hours post dosing.
- of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Plasma Nterminal pro-brain natriuretic peptide (NTproBNP):
Time Frame: 0 and optional 24 hours post dosing.
- 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):
- 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
Parti 1: To assess the safety and tolerability of LCZ696 in pediatric patients with heart failure
- 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.
- 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.
- 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.
Part 1 is open label
A patient will be considered to have completed the study when the patient has completed the last visit planned in the protocol.
F.1.1.4.1 Number of subjects for this age range: 120
F.1.1.5.1 Number of subjects for this age range: 120
Written informed consent by parent(s)/legal guardian(s) for the patient must be obtained before any study-specific assessment is performed. A consent or assent may also be required for some patients
depending upon their age and local requirements
Continuing care should be provided by Investigator and/or other caring physician. The patient can be placed on an ACEI or ARB for HF treatment as determined by the caring physician. Standard HF medication / treatment can started at end of study.
N. Date of Competent Authority Decision 2017-03-27
N. Date of Ethics Committee Opinion 2017-03-08
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