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

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

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.

Study Overview

• Status: Completed
• Conditions: Pediatric Heart Failure
• Intervention / Treatment: Drug: Placebo of LCZ696; Drug: Placebo of Enalapril; Drug: LCZ696; Drug: Enalapril; Drug: LCZ696

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 393
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Ramos Mejia, Buenos Aires, Argentina, B1704ETD
      • Novartis Investigative Site
  • Provincia De Salta
    • Ciudad de Salta, Provincia De Salta, Argentina, A4406BPF
      • Novartis Investigative Site
• Austria
  • Innsbruck, Austria, 6020
    • Novartis Investigative Site
• Bulgaria
  • Sofia, Bulgaria, 1309
    • Novartis Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1C9
      • Novartis Investigative Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Novartis Investigative Site
• China
  • Beijing, China, 100037
    • Novartis Investigative Site
  • Shanghai, China, 200127
    • Novartis Investigative Site
  • Shanghai, China, 200062
    • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510623
      • Novartis Investigative Site
• Croatia
  • Zagreb, Croatia, 10000
    • Novartis Investigative Site
• Czechia
  • Praha 5, Czechia, 150 06
    • Novartis Investigative Site
• Finland
  • Helsinki, Finland, 00290
    • Novartis Investigative Site
• France
  • Montpellier, France, 34295 CEDEX 5
    • Novartis Investigative Site
  • Paris, France, 75015
    • Novartis Investigative Site
  • Pessac, France, 33600
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Freiburg, Germany, 79106
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Leipzig, Germany, 04289
    • Novartis Investigative Site
  • Stuttgart, Germany, 70174
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H 1096
    • Novartis Investigative Site
• India
  • Delhi
    • New Delhi, Delhi, India, 110 060
      • Novartis Investigative Site
    • New Delhi, Delhi, India, 110076
      • Novartis Investigative Site
  • Gujarat
    • Ahmedabad, Gujarat, India, 380 060
      • Novartis Investigative Site
  • Kerala
    • Kochi, Kerala, India, 682041
      • Novartis Investigative Site
• Israel
  • Be'er-Sheva, Israel, 84101
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • BG
    • Bergamo, BG, Italy, 24127
      • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50132
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00165
      • Novartis Investigative Site
  • TO
    • Torino, TO, Italy, 10126
      • Novartis Investigative Site
• Japan
  • Saitama, Japan, 330 8777
    • Novartis Investigative Site
  • Aichi
    • Obu, Aichi, Japan, 474 8710
      • Novartis Investigative Site
  • Hokkaido
    • Sapporo city, Hokkaido, Japan, 060 8648
      • Novartis Investigative Site
  • Nagasaki
    • Omura, Nagasaki, Japan, 856-8562
      • Novartis Investigative Site
  • Tokyo
    • Bunkyo ku, Tokyo, Japan, 113 8655
      • Novartis Investigative Site
    • Setagaya-ku, Tokyo, Japan, 157-8535
      • Novartis Investigative Site
    • Shinjuku ku, Tokyo, Japan, 162 8666
      • Novartis Investigative Site
  • Toyama
    • Toyama-city, Toyama, Japan, 930-0194
      • Novartis Investigative Site
• Jordan
  • JOR
    • Amman, JOR, Jordan, 11183
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
  • Gyeongsangnam Do
    • Yangsan, Gyeongsangnam Do, Korea, Republic of, 50612
      • Novartis Investigative Site
• Lebanon
  • Beirut, Lebanon
    • Novartis Investigative Site
  • El Achrafîyé, Lebanon, 166830
    • Novartis Investigative Site
• Poland
  • Gdansk, Poland, 80-952
    • Novartis Investigative Site
  • Warszawa, Poland, 04 730
    • Novartis Investigative Site
• Portugal
  • Coimbra, Portugal, 3000 075
    • Novartis Investigative Site
  • Lisboa, Portugal, 1169 024
    • Novartis Investigative Site
  • Lisboa
    • Carnaxide, Lisboa, Portugal, 2799 523
      • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 125412
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 197341
    • Novartis Investigative Site
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11211
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 229899
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Andalucia
    • Cordoba, Andalucia, Spain, 14004
      • Novartis Investigative Site
  • Cataluna
    • Barcelona, Cataluna, Spain, 08950
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Switzerland
  • Lausanne, Switzerland, 1011
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung City, Taiwan, 83301
    • Novartis Investigative Site
  • Taipei, Taiwan, 10041
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Bangkok
    • Bangkoknoi, Bangkok, Thailand, 10700
      • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06490
    • Novartis Investigative Site
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
  • Konak, Turkey, 35210
    • Novartis Investigative Site
• United States
  • California
    • Loma Linda, California, United States, 92354
      • Novartis Investigative Site
    • Los Angeles, California, United States, 90027
      • Novartis Investigative Site
    • Los Angeles, California, United States, 90095
      • Novartis Investigative Site
    • Palo Alto, California, United States, 94304
      • Novartis Investigative Site
    • San Diego, California, United States, 92123
      • Novartis Investigative Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Novartis Investigative Site
  • Florida
    • Gainesville, Florida, United States, 32610
      • Novartis Investigative Site
    • Miami, Florida, United States, 33136
      • Novartis Investigative Site
    • Saint Petersburg, Florida, United States, 33701
      • Novartis Investigative Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Novartis Investigative Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Novartis Investigative Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5238
      • Novartis Investigative Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Novartis Investigative Site
    • Rochester, Minnesota, United States, 55905
      • Novartis Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Novartis Investigative Site
  • New York
    • New York, New York, United States, 10029
      • Novartis Investigative Site
    • New York, New York, United States, 10032
      • Novartis Investigative Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Novartis Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Novartis Investigative Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104 4399
      • Novartis Investigative Site
    • Pittsburgh, Pennsylvania, United States, 15224
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75235
      • Novartis Investigative Site
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Novartis Investigative Site
  • Washington
    • Seattle, Washington, United States, 98105
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part 1: LCZ696 open label; 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.	Drug: LCZ696; LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules); Drug: Enalapril; Enalapril tablets: 2.5 mg, 5 mg, 10 mg dosage strengths; Drug: LCZ696; LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules), tablets: 50 mg, 100 mg, 200 mg dosage strengths
ACTIVE_COMPARATOR: Part 2: Enalapril; 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.	Drug: Placebo of LCZ696; Drug: Enalapril; Enalapril tablets: 2.5 mg, 5 mg, 10 mg dosage strengths
EXPERIMENTAL: Part 2: LCZ696; 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.	Drug: Placebo of Enalapril; Drug: LCZ696; LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules); Drug: LCZ696; LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules), tablets: 50 mg, 100 mg, 200 mg dosage strengths

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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 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).	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 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).	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 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.	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 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.	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 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.	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 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.	Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2
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.	Baseline (0 hrs pre dose) and optional 24 hrs post dosing on Day 1 of Period 1 and Period 2
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.	Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2
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.	Baseline (0 hrs pre dose), 4 to 8 hrs post dose on Day 1 of Period 1 and Period 2
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.	Up to 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From first dose to 30 days after last dose of study drug in 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.	From first dose to 30 days after last dose of study drug in Part 2 (up to 56 weeks)
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.	52 weeks
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).	Baseline, Week 4, 12, 24, 36, and 52
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).	Baseline, Week 4, 12, 24, 36, and 52
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: 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
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: 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
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: 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
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: 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
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: 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
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: 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
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.	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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 3, 2016
• Primary Completion (ACTUAL): January 3, 2022
• Study Completion (ACTUAL): January 3, 2022

Study Registration Dates

• First Submitted: February 4, 2016
• First Submitted That Met QC Criteria: February 4, 2016
• First Posted (ESTIMATE): February 9, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 10, 2023
• Last Update Submitted That Met QC Criteria: January 12, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: reduced ejection fraction; Pediatric Heart failure,; systemic left ventricle,
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Enalaprilat; Enalapril; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696B2319; 2015-004207-22 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes