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 |
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E.1.1.1 | Medical condition in easily understood language |
Pediatric heart failure (HF) |
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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 | 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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E.2.2 | Secondary objectives of the trial |
Part 1: To assess the safety and tolerability of LCZ696 in pediatric
patients with HF
Part 2: To determine whether LCZ696 is superior to enalapril in delaying
time to first occurrence of the composite of either Category 1 or 2 events
(e.g. death, worsening HF)
Part 2: To determine whether LCZ696 is superior to enalapril for
improving NYHA (New York Heart Association)/Ross functional class
Part 2: To determine whether LCZ696 is superior to enalapril for
improving the Patient Global Impression of Severity (PGIS) score
Part 2: To characterize the population PK of LCZ696 exposure in pediatric patients with HF, including an assessment of steady-state sparse PK data in a subset of Group 2 patients
Part 2: To assess the safety and tolerability of LCZ696 compared to enalapril in pediatric patients with HF |
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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 |
Palatability and acceptability sub-study (applicable only to sites
participating in the palatability and acceptability sub-study)
The purpose of this sub-study is to explore the palatability and overall
acceptability of the LCZ696/placebo liquid formulation and to explore
the overall acceptability of the LCZ696/placebo granules formulation in a
representative subsets of patients from the three age groups enrolled in
Part 2 (Efficacy) of the main study CLCZ696B2319. |
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E.3 | Principal inclusion criteria |
-Male or female, inpatient or outpatient, 1 month to < 18 years of age
- 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) any time prior
to screening
- Systemic left ventricular ejection fraction ≤ 45% or fractional
shortening ≤22.5%
(assessed by most recent echocardiography, MRI, MUGA or left
ventricular angiogram within 1 month before patient begins Part 2).
[Note: The study will target enrollment of approximately 80% patients
with a
systemic left ventricular ejection fraction (EF) ≤ 40% or fractional
shortening ≤20% for Part 2 only].
- Biventricular physiology with systemic left ventricle
- 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 a daily dose equivalent of at least enalapril 0.2 mg/kg prior to the
LCZ696 3.1 mg/kg single dose assessment.
For Part 1 PK/PD, patients in Group 3 must be currently treated with a
daily dose equivalent of at least enalapril 0.1 mg/kg prior to the LCZ696
1.6 mg/kg single dose assessment
Sub-study entry criteria:
The patient is assigned at randomization in Part 2 of the main study
CLCZ696B2319 to one of the following formulations:
LCZ696/ placebo liquid
OR
CZ696/ placebo granules
- Participant and/or participant's parent/caregiver capable of
understanding the
assessment procedures and participant obligations.
- Must not have any impairment in swallowing either solids or liquids as
a consequence of acute or chronic illness and /or the inability to
participate in the
palatability/acceptability assessment due to a condition that includes
loss or alteration of taste. |
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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
- For part 2 only, 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
- For Part 2 only, 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
- Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they are using highly effective
methods of contraception during dosing of investigational drug
- Patient breastfed by a mother taking ACEI
Other protocol defined inclusion/exclusion criteria may apply. |
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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. |
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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 |
|
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.
- Population PK of LCZ696 exposure in pediatric patients with HF,
including an assessment of steady-state sparse PK data in a subset of
Group 2
patients which allows for an estimate clearance and total exposure to
further confirm the target dose for this age group. Available BioMarker
data will also be
assessed |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time to first occurrence of Cat 1 or Cat 2 event: 52w.
Change from baseline in NYHA/Ross functclass: Baseline to 52w.
Change from baseline in (PGIS) scale: Baseline to 52w.
Pop 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), Max 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 0 to the end of the dosing interval
tau at steady state (AUCtau,ss): wks 4, 12, 52. - steady-state sparse PK data in a subset of Group 2 pts: wk 8 or a subsequent visit) |
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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 | 2 |
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 |
Czechia |
Egypt |
Finland |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Japan |
Jordan |
Korea, Republic of |
Lebanon |
Malaysia |
Netherlands |
Norway |
Philippines |
Poland |
Russian Federation |
Saudi Arabia |
Singapore |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
United Arab Emirates |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |