Back to results

Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LCZ696 Followed by a 52-week, Double-blind Study of LCZ696 Compared With Enalapril in Pediatric Patients With Heart Failure

Primary Purpose

Pediatric Heart Failure

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

LCZ696

Enalapril

Placebo of LCZ696

Placebo of Enalapril

LCZ696

About this trial

This is an interventional treatment trial for Pediatric Heart Failure focused on measuring Pediatric Heart failure,, systemic left ventricle,, reduced ejection fraction

Eligibility Criteria

1 Month - 17 Years (Child)All SexesDoes not accept healthy volunteers

Key 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 study: Patients must be treated with an ACEI or ARB prior to screening. 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 administration. Group 3 patients will participate in LCZ696 0.8 mg/kg and not LCZ696 3.1 mg/kg.
Biventricular physiology with systemic left ventricle

Key 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
History of angioedema
Allergy or hypersensitivity to ACEI / ARB

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Experimental

Arm Label

Part 1: LCZ696 open label

Part 2: Enalapril

Part 2: LCZ696

Arm Description

LCZ696 open label: For Age Groups 1 and 2, either 1) 0.8 mg/kg or 2) 3.1 mg/kg or both. For Age Group 3, either 1) 0.4 mg/kg or 2) 1.6 mg/kg or both. After LCZ696 PK assessment, patients will be maintained on open-label Enalapril provided locally by the study site, or standard of care also provided locally by the study site, for heart failure treatment, if patient intended to participate in Part 2.

The target dose for enalapril is 0.2 mg/kg bid (0.4 mg/kg total daily dose) with a maximum dose of 10 mg bid (20 mg total daily dose). Administered in a double-blind fashion.

LCZ696 3.125 mg granules and adult formulation (50, 100, 200 mg) can be given based on patient weight. Administered in a double-blind fashion.

Outcomes

Primary Outcome Measures

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Maximum Drug Concentration in Plasma (Cmax)

The analyses of Cmax was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s).

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Time to Maximum Plasma Concentration (Tmax)

The analyses of Tmax was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s).

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)

The analyses of AUCinf was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s).

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Number of Participants With Area Under the Plasma Concentration-time Curve From Time Zero to Last (AUClast)

As prespecified in protocol and SAP the analysis of this outcome measure was done based on dose of LCZ696 administered within the different age groups.

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, and Valsartan): Clearance From Plasma (CL/F)

The analyses was based on plasma concentrations of two sacubitril/valsartan analytes (AHU377 (sacubitril), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s). CL/F was not estimated for LBQ657 as it is a metabolite.

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril): Time Required to Drug Concentration to Decrease by Half (T 1/2)

The analyses of T1/2 was based on plasma concentrations of sacubitril. The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s). T1/2 for other analytes of LCZ696 (LBQ657 and Valsartan) was not estimable due to the short sample collection timeframe.

Part 1: Pharmacodynamics (PD) of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma B-type Natriuretic Peptide (BNP)

Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma BNP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.

Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma N-terminal Pro-brain Natriuretic Peptide (NTproBNP)

Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma NTproBNP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.

Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma Cyclic Guanosine Monophosphate (cGMP)

Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma cGMP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.

Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Urine cGMP

Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included urine cGMP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.

Part 2: Percentage of Participants With Worst Event in Each Category Based on Global Ranking

Global ranking is based on 5 categories ranking worst to best outcome:Category 1:Death; United Network for Organ Sharing(UNOS)status 1A listing for heart transplant or equivalent; ventricular assist device(VAD)/extracorporeal membrane oxygenation(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. Category 3:Worsened; worse New York Heart Association(NYHA)/Ross or worse Patient Global Impression of Severity(PGIS); and further ranking by Pediatric Quality of Life Inventory(PedsQL)physical functioning domain.Category 4:Unchanged; unchanged NYHA/Ross and unchanged PGIS; and further ranking by PedsQL physical functioning domain. Category 5:Improved; improved NYHA/Ross or improved PGIS(neither can be worse);and further ranking by PedsQL physical functioning domain. Participants with worst event in each category are reported here.

Secondary Outcome Measures

Part 1: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)

An adverse event (AE) is any untoward medical occurrence associated with use of a drug in humans, whether considered drug related or not, that occurs after a participant provides informed consent. TEAEs during part 1 are defined as any recorded AE with its start date (recorded or imputed) later than or equal to the date of the first dose of the study drug within part 1 and its start date prior to or equal to the end date of the part 1.

Part 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)

An AE is any untoward medical occurrence associated with use of a drug in humans, whether or not considered drug related, that occurs after a participant provides informed consent. TEAEs during part 2 are defined as any recorded AE with its start date (recorded or imputed) later than or equal to the date of the first dose of the study drug within part 2 and its start date prior to or equal to the end date of part 2.

Part 2: Exposure-adjusted Incidence Rate of Category 1 or Category 2 Event

The exposure adjusted incidence rate is calculated as number of participants with at least one event divided by total participant years across all participants. Category 1: Death; 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: WHF; defined by signs and symptoms of WHF that requires an intensification of HF therapy.

Part 2: Percentage of Participants With Change From Baseline in New York Heart Association (NYHA)/Ross Functional Class

NYHA classification is a subjective physician's assessment of participant's functional capacity and symptomatic status and can change frequently over time. NYHA is tool that classifies participants with heart failure into one of four classes according to their degree of symptoms at rest and with activity. Class I: No limitations of physical activity. Class 2: May experience fatigue, palpitations, dyspnea, or angina during moderate exercise but not during rest. Class 3: Symptoms with minimal exertion that interfere with normal daily activity. Class 4: Unable to carry out any physical activity because they typically have symptoms of HF at rest that worsen with any exertion. Participants with change from baseline were classified as improved (shifted from higher to lower class), unchanged (no change in class) or worsened (shifted from lower to higher class).

Part 2: Percentage of Participants With Change From Baseline in Patient Global Impression of Severity (PGIS) Score

PGIS of Heart Failure Symptoms is a 1-item questionnaire to assess the participant's impression of symptoms severity, specifically: shortness of breath, fatigue and swelling. The PGI-S asks the participant to choose one response that best describes how his/her heart failure symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-point scale, ranging from 'Not at all' (1) to 'Very severe' (5). C1 = none (good), C2 = mild, C3 = moderate, C4 = severe, C5 = very severe (bad). Percentage of participants by change in score are reported. Participants with change from baseline were classified as improved (shifted from higher to score), unchanged (no change in score) or worsened (shifted from lower to higher score).

Part 1 and Part 2: Population PK of LCZ696 Analytes: Clearance From Plasma (CL)

The analyses of CL was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.

Part 1 and Part 2: Population PK of LCZ696 Analytes: Volume of Distribution in Steady State

The analyses of volume of distribution was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.

Part 1 and Part 2: Population PK of LCZ696 Analytes: Absorption Rate Constant (Ka)

The analyses of Ka was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.

Part 1 and Part 2: Population PK of LCZ696 Analytes: Time Required to Drug Concentration to Decrease by Half (T 1/2)

The analyses of T1/2 was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.

Part 1 and Part 2: Population PK of LCZ696 Analytes: Maximum Drug Concentration in Plasma at Steady State (Cmax,ss)

The analyses of Cmax was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.

Part 1 and Part 2: Population PK of LCZ696 Analytes: Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss)

The analyses of Cmin was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.

Part 1 and Part 2: Population PK of LCZ696 Analytes: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady State (AUCtau,ss)

The analyses of AUCtau was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.

Full Information

NCT ID

NCT02678312

First Posted

February 4, 2016

Last Updated

January 12, 2023

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT02678312

Brief Title

Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LCZ696 Followed by a 52-week, Double-blind Study of LCZ696 Compared With Enalapril in Pediatric Patients With Heart Failure

Official Title

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 From 1 Month to < 18 Years of Age With Heart Failure Due to Systemic Left Ventricle Systolic Dysfunction

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Completed

Study Start Date

November 3, 2016 (Actual)

Primary Completion Date

January 3, 2022 (Actual)

Study Completion Date

January 3, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study consists of two parts (Part 1 and Part 2). The purpose of Part 1 is to evaluate the way the body absorbs, distributes, metabolizes and removes the drug LCZ696. This will help determine the proper dose of LCZ696 for Part 2 of the study. The purpose for Part 2 is to compare the effectiveness and safety of LCZ696 with enalapril in a double-blind manner, in pediatric heart failure patients over 52 weeks of treatment.

Detailed Description

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pediatric Heart Failure

Keywords

Pediatric Heart failure,, systemic left ventricle,, reduced ejection fraction

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

393 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: LCZ696 open label

Arm Type

Experimental

Arm Description

Arm Title

Part 2: Enalapril

Arm Type

Active Comparator

Arm Description

The target dose for enalapril is 0.2 mg/kg bid (0.4 mg/kg total daily dose) with a maximum dose of 10 mg bid (20 mg total daily dose). Administered in a double-blind fashion.

Arm Title

Part 2: LCZ696

Arm Type

Experimental

Arm Description

LCZ696 3.125 mg granules and adult formulation (50, 100, 200 mg) can be given based on patient weight. Administered in a double-blind fashion.

Intervention Type

Drug

Intervention Name(s)

LCZ696

Intervention Description

LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules)

Intervention Type

Drug

Intervention Name(s)

Enalapril

Intervention Description

Enalapril tablets: 2.5 mg, 5 mg, 10 mg dosage strengths

Intervention Type

Drug

Intervention Name(s)

Placebo of LCZ696

Intervention Type

Drug

Intervention Name(s)

Placebo of Enalapril

Intervention Type

Drug

Intervention Name(s)

LCZ696

Intervention Description

LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules), tablets: 50 mg, 100 mg, 200 mg dosage strengths

Primary Outcome Measure Information:

Title

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Maximum Drug Concentration in Plasma (Cmax)

Description

Time Frame

Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2

Title

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Time to Maximum Plasma Concentration (Tmax)

Description

Time Frame

Title

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)

Description

Time Frame

Title

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Number of Participants With Area Under the Plasma Concentration-time Curve From Time Zero to Last (AUClast)

Description

As prespecified in protocol and SAP the analysis of this outcome measure was done based on dose of LCZ696 administered within the different age groups.

Time Frame

Title

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, and Valsartan): Clearance From Plasma (CL/F)

Description

Time Frame

Title

Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril): Time Required to Drug Concentration to Decrease by Half (T 1/2)

Description

Time Frame

Title

Part 1: Pharmacodynamics (PD) of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma B-type Natriuretic Peptide (BNP)

Description

Time Frame

Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2

Title

Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma N-terminal Pro-brain Natriuretic Peptide (NTproBNP)

Description

Time Frame

Baseline (0 hrs pre dose) and optional 24 hrs post dosing on Day 1 of Period 1 and Period 2

Title

Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma Cyclic Guanosine Monophosphate (cGMP)

Description

Time Frame

Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2

Title

Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Urine cGMP

Description

Time Frame

Baseline (0 hrs pre dose), 4 to 8 hrs post dose on Day 1 of Period 1 and Period 2

Title

Part 2: Percentage of Participants With Worst Event in Each Category Based on Global Ranking

Description

Time Frame

Up to 52 weeks

Secondary Outcome Measure Information:

Title

Part 1: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)

Description

Time Frame

From first dose to 30 days after last dose of study drug in Part 1

Title

Part 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)

Description

Time Frame

From first dose to 30 days after last dose of study drug in Part 2 (up to 56 weeks)

Title

Part 2: Exposure-adjusted Incidence Rate of Category 1 or Category 2 Event

Description

Time Frame

52 weeks

Title

Part 2: Percentage of Participants With Change From Baseline in New York Heart Association (NYHA)/Ross Functional Class

Description

Time Frame

Baseline, Week 4, 12, 24, 36, and 52

Title

Part 2: Percentage of Participants With Change From Baseline in Patient Global Impression of Severity (PGIS) Score

Description

Time Frame

Baseline, Week 4, 12, 24, 36, and 52

Title

Part 1 and Part 2: Population PK of LCZ696 Analytes: Clearance From Plasma (CL)

Description

Time Frame

Part 1: Age group 1- Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3- Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Part 2: Weeks 2, 8, 12, 52

Title

Part 1 and Part 2: Population PK of LCZ696 Analytes: Volume of Distribution in Steady State

Description

Time Frame

Title

Part 1 and Part 2: Population PK of LCZ696 Analytes: Absorption Rate Constant (Ka)

Description

Time Frame

Title

Part 1 and Part 2: Population PK of LCZ696 Analytes: Time Required to Drug Concentration to Decrease by Half (T 1/2)

Description

Time Frame

Title

Part 1 and Part 2: Population PK of LCZ696 Analytes: Maximum Drug Concentration in Plasma at Steady State (Cmax,ss)

Description

Time Frame

Title

Part 1 and Part 2: Population PK of LCZ696 Analytes: Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss)

Description

Time Frame

Title

Part 1 and Part 2: Population PK of LCZ696 Analytes: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady State (AUCtau,ss)

Description

Time Frame

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Month

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

Key Inclusion Criteria: Chronic heart failure (CHF) resulting from left ventricular systolic dysfunction, and receiving chronic HF therapy (if not newly diagnosed) New York Heart Association (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 ≤ 45% or fractional shortening ≤22.5% For Part 1 study: Patients must be treated with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARB) prior to screening. 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 administration. Group 3 patients will participate in LCZ696 0.8 mg/kg and not LCZ696 3.1 mg/kg. Biventricular physiology with systemic left ventricle Key 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 History of angioedema Allergy or hypersensitivity to ACEI / ARB

Facility Information:

Facility Name

Novartis Investigative Site

City

Loma Linda

State/Province

California

ZIP/Postal Code

92354

Country

United States

Facility Name

Novartis Investigative Site

City

Los Angeles

State/Province

California

ZIP/Postal Code

90027

Country

United States

Facility Name

Novartis Investigative Site

City

Los Angeles

State/Province

California

ZIP/Postal Code

90095

Country

United States

Facility Name

Novartis Investigative Site

City

Palo Alto

State/Province

California

ZIP/Postal Code

94304

Country

United States

Facility Name

Novartis Investigative Site

City

San Diego

State/Province

California

ZIP/Postal Code

92123

Country

United States

Facility Name

Novartis Investigative Site

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

Novartis Investigative Site

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

Facility Name

Novartis Investigative Site

City

Miami

State/Province

Florida

ZIP/Postal Code

33136

Country

United States

Facility Name

Novartis Investigative Site

City

Saint Petersburg

State/Province

Florida

ZIP/Postal Code

33701

Country

United States

Facility Name

Novartis Investigative Site

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Novartis Investigative Site

City

Indianapolis

State/Province

Indiana

ZIP/Postal Code

46202

Country

United States

Facility Name

Novartis Investigative Site

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Novartis Investigative Site

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48109-5238

Country

United States

Facility Name

Novartis Investigative Site

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

Facility Name

Novartis Investigative Site

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

Facility Name

Novartis Investigative Site

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Facility Name

Novartis Investigative Site

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

Facility Name

Novartis Investigative Site

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

Novartis Investigative Site

City

Charlotte

State/Province

North Carolina

ZIP/Postal Code

28203

Country

United States

Facility Name

Novartis Investigative Site

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

Facility Name

Novartis Investigative Site

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104 4399

Country

United States

Facility Name

Novartis Investigative Site

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15224

Country

United States

Facility Name

Novartis Investigative Site

City

Dallas

State/Province

Texas

ZIP/Postal Code

75235

Country

United States

Facility Name

Novartis Investigative Site

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84113

Country

United States

Facility Name

Novartis Investigative Site

City

Seattle

State/Province

Washington

ZIP/Postal Code

98105

Country

United States

Facility Name

Novartis Investigative Site

City

Ramos Mejia

State/Province

Buenos Aires

ZIP/Postal Code

B1704ETD

Country

Argentina

Facility Name

Novartis Investigative Site

City

Ciudad de Salta

State/Province

Provincia De Salta

ZIP/Postal Code

A4406BPF

Country

Argentina

Facility Name

Novartis Investigative Site

City

Innsbruck

ZIP/Postal Code

6020

Country

Austria

Facility Name

Novartis Investigative Site

City

Sofia

ZIP/Postal Code

1309

Country

Bulgaria

Facility Name

Novartis Investigative Site

City

Edmonton

State/Province

Alberta

ZIP/Postal Code

T6G 1C9

Country

Canada

Facility Name

Novartis Investigative Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 1X8

Country

Canada

Facility Name

Novartis Investigative Site

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510623

Country

China

Facility Name

Novartis Investigative Site

City

Beijing

ZIP/Postal Code

100037

Country

China

Facility Name

Novartis Investigative Site

City

Shanghai

ZIP/Postal Code

200062

Country

China

Facility Name

Novartis Investigative Site

City

Shanghai

ZIP/Postal Code

200127

Country

China

Facility Name

Novartis Investigative Site

City

Zagreb

ZIP/Postal Code

10000

Country

Croatia

Facility Name

Novartis Investigative Site

City

Praha 5

ZIP/Postal Code

150 06

Country

Czechia

Facility Name

Novartis Investigative Site

City

Helsinki

ZIP/Postal Code

00290

Country

Finland

Facility Name

Novartis Investigative Site

City

Montpellier

ZIP/Postal Code

34295 CEDEX 5

Country

France

Facility Name

Novartis Investigative Site

City

Paris

ZIP/Postal Code

75015

Country

France

Facility Name

Novartis Investigative Site

City

Pessac

ZIP/Postal Code

33600

Country

France

Facility Name

Novartis Investigative Site

City

Berlin

ZIP/Postal Code

13353

Country

Germany

Facility Name

Novartis Investigative Site

City

Erlangen

ZIP/Postal Code

91054

Country

Germany

Facility Name

Novartis Investigative Site

City

Freiburg

ZIP/Postal Code

79106

Country

Germany

Facility Name

Novartis Investigative Site

City

Heidelberg

ZIP/Postal Code

69120

Country

Germany

Facility Name

Novartis Investigative Site

City

Leipzig

ZIP/Postal Code

04289

Country

Germany

Facility Name

Novartis Investigative Site

City

Stuttgart

ZIP/Postal Code

70174

Country

Germany

Facility Name

Novartis Investigative Site

City

Budapest

ZIP/Postal Code

H 1096

Country

Hungary

Facility Name

Novartis Investigative Site

City

New Delhi

State/Province

Delhi

ZIP/Postal Code

110 060

Country

India

Facility Name

Novartis Investigative Site

City

New Delhi

State/Province

Delhi

ZIP/Postal Code

110076

Country

India

Facility Name

Novartis Investigative Site

City

Ahmedabad

State/Province

Gujarat

ZIP/Postal Code

380 060

Country

India

Facility Name

Novartis Investigative Site

City

Kochi

State/Province

Kerala

ZIP/Postal Code

682041

Country

India

Facility Name

Novartis Investigative Site

City

Be'er-Sheva

ZIP/Postal Code

84101

Country

Israel

Facility Name

Novartis Investigative Site

City

Bergamo

State/Province

ZIP/Postal Code

24127

Country

Italy

Facility Name

Novartis Investigative Site

City

Bologna

State/Province

ZIP/Postal Code

40138

Country

Italy

Facility Name

Novartis Investigative Site

City

Firenze

State/Province

ZIP/Postal Code

50132

Country

Italy

Facility Name

Novartis Investigative Site

City

Milano

State/Province

ZIP/Postal Code

20162

Country

Italy

Facility Name

Novartis Investigative Site

City

Padova

State/Province

ZIP/Postal Code

35128

Country

Italy

Facility Name

Novartis Investigative Site

City

Roma

State/Province

ZIP/Postal Code

00165

Country

Italy

Facility Name

Novartis Investigative Site

City

Torino

State/Province

ZIP/Postal Code

10126

Country

Italy

Facility Name

Novartis Investigative Site

City

Napoli

ZIP/Postal Code

80131

Country

Italy

Facility Name

Novartis Investigative Site

City

Obu

State/Province

Aichi

ZIP/Postal Code

474 8710

Country

Japan

Facility Name

Novartis Investigative Site

City

Sapporo city

State/Province

Hokkaido

ZIP/Postal Code

060 8648

Country

Japan

Facility Name

Novartis Investigative Site

City

Omura

State/Province

Nagasaki

ZIP/Postal Code

856-8562

Country

Japan

Facility Name

Novartis Investigative Site

City

Bunkyo ku

State/Province

Tokyo

ZIP/Postal Code

113 8655

Country

Japan

Facility Name

Novartis Investigative Site

City

Setagaya-ku

State/Province

Tokyo

ZIP/Postal Code

157-8535

Country

Japan

Facility Name

Novartis Investigative Site

City

Shinjuku ku

State/Province

Tokyo

ZIP/Postal Code

162 8666

Country

Japan

Facility Name

Novartis Investigative Site

City

Toyama-city

State/Province

Toyama

ZIP/Postal Code

930-0194

Country

Japan

Facility Name

Novartis Investigative Site

City

Saitama

ZIP/Postal Code

330 8777

Country

Japan

Facility Name

Novartis Investigative Site

City

Amman

State/Province

JOR

ZIP/Postal Code

11183

Country

Jordan

Facility Name

Novartis Investigative Site

City

Yangsan

State/Province

Gyeongsangnam Do

ZIP/Postal Code

50612

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Seoul

ZIP/Postal Code

03080

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Seoul

ZIP/Postal Code

03722

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Seoul

ZIP/Postal Code

06351

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Beirut

Country

Lebanon

Facility Name

Novartis Investigative Site

City

El Achrafîyé

ZIP/Postal Code

166830

Country

Lebanon

Facility Name

Novartis Investigative Site

City

Gdansk

ZIP/Postal Code

80-952

Country

Poland

Facility Name

Novartis Investigative Site

City

Warszawa

ZIP/Postal Code

04 730

Country

Poland

Facility Name

Novartis Investigative Site

City

Carnaxide

State/Province

Lisboa

ZIP/Postal Code

2799 523

Country

Portugal

Facility Name

Novartis Investigative Site

City

Coimbra

ZIP/Postal Code

3000 075

Country

Portugal

Facility Name

Novartis Investigative Site

City

Lisboa

ZIP/Postal Code

1169 024

Country

Portugal

Facility Name

Novartis Investigative Site

City

Moscow

ZIP/Postal Code

125412

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Saint Petersburg

ZIP/Postal Code

197341

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Riyadh

ZIP/Postal Code

11211

Country

Saudi Arabia

Facility Name

Novartis Investigative Site

City

Singapore

ZIP/Postal Code

229899

Country

Singapore

Facility Name

Novartis Investigative Site

City

Cordoba

State/Province

Andalucia

ZIP/Postal Code

14004

Country

Spain

Facility Name

Novartis Investigative Site

City

Barcelona

State/Province

Cataluna

ZIP/Postal Code

08950

Country

Spain

Facility Name

Novartis Investigative Site

City

Barcelona

State/Province

Catalunya

ZIP/Postal Code

08035

Country

Spain

Facility Name

Novartis Investigative Site

City

Madrid

ZIP/Postal Code

28009

Country

Spain

Facility Name

Novartis Investigative Site

City

Madrid

ZIP/Postal Code

28046

Country

Spain

Facility Name

Novartis Investigative Site

City

Lausanne

ZIP/Postal Code

1011

Country

Switzerland

Facility Name

Novartis Investigative Site

City

Kaohsiung City

ZIP/Postal Code

83301

Country

Taiwan

Facility Name

Novartis Investigative Site

City

Taipei

ZIP/Postal Code

10041

Country

Taiwan

Facility Name

Novartis Investigative Site

City

Bangkoknoi

State/Province

Bangkok

ZIP/Postal Code

10700

Country

Thailand

Facility Name

Novartis Investigative Site

City

Bangkok

ZIP/Postal Code

10400

Country

Thailand

Facility Name

Novartis Investigative Site

City

Ankara

ZIP/Postal Code

06490

Country

Turkey

Facility Name

Novartis Investigative Site

City

Izmir

ZIP/Postal Code

35040

Country

Turkey

Facility Name

Novartis Investigative Site

City

Konak

ZIP/Postal Code

35210

Country

Turkey

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel based on scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Learn more about this trial

We'll reach out to this number within 24 hrs

Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LCZ696 Followed by a 52-week, Double-blind Study of LCZ696 Compared With Enalapril in Pediatric Patients With Heart Failure

Pediatric Heart Failure

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial