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

• ClinicalTrials.gov Identifier: NCT02678312
• Recruitment Status: Completed
• First Posted: February 9, 2016
• Results First Posted: February 10, 2023
• Last Update Posted: February 10, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: February 4, 2016
• First Posted Date: February 9, 2016
• Results First Submitted Date: July 1, 2022
• Results First Posted Date: February 10, 2023
• Last Update Posted Date: February 10, 2023
• Actual Study Start Date: November 3, 2016
• Actual Primary Completion Date: January 3, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 12, 2023)

• Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Maximum Drug Concentration in Plasma (Cmax) [ 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 ]
  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) [ 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 ]
  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) [ 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 ]
  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) [ 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 ]
  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) [ 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 ]
  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) [ 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 ]
  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) [ Time Frame: Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2 ]
  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) [ Time Frame: Baseline (0 hrs pre dose) and optional 24 hrs post dosing on Day 1 of Period 1 and Period 2 ]
  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) [ Time Frame: Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2 ]
  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 [ Time Frame: Baseline (0 hrs pre dose), 4 to 8 hrs post dose on Day 1 of Period 1 and Period 2 ]
  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 [ Time Frame: Up to 52 weeks ]
  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.

Original Primary Outcome Measures (submitted: February 4, 2016)

• Part 1: Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Maximum drug concentration in plasma (Cmax) [ Time Frame: 0, 0.5, 1, 2, 4, 8, 10, and optional 24 hours post dosing ]
  Cmax will be determined for LCZ696 analytes (sacubitril, LBQ657, and valsartan) by using non-compartmental methods.
• Part 1: Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Time to maximum plasma concentration (Tmax) [ Time Frame: 0, 0.5, 1, 2, 4, 8, 10, and optional 24 hours post dosing ]
  Tmax will be determined for LCZ696 analytes (sacubitril, LBQ657, and valsartan) by using non-compartmental methods.
• Part 1: 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) [ Time Frame: 0, 0.5, 1, 2, 4, 8, 10, and optional 24 hours post dosing ]
  AUCinf and AUClast will be determined for LCZ696 analytes (sacubitril, LBQ657, and valsartan) by using non-compartmental methods.
• Part 1: Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Clearance from plasma (CL/F) [ Time Frame: 0, 0.5, 1, 2, 4, 8, 10, and optional 24 hours post dosing ]
  CL/F will be determined for LCZ696 analytes (sacubitril, LBQ657, and valsartan) by using non-compartmental methods.
• Part 1: Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Time required to drug concentration to decrease by half (T 1/2) [ Time Frame: 0, 0.5, 1, 2, 4, 8, 10, and optional 24 hours post dosing ]
  T 1/2 will be determined for LCZ696 analytes (sacubitril, LBQ657, and valsartan) by using non-compartmental methods
• Part 1: Pharmacodynamics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Plasma N-terminal pro-brain natriuretic peptide (NTproBNP) [ Time Frame: 0, 4, 8, optional 24 hours post dosing ]
  The 24 hour post dose is optional depending on blood volume restrictions.
• Part 1: Pharmacodynamics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Plasma cyclic guanosine monophosphate (cGMP) [ Time Frame: 0, 4, 8, optional 24 hours post dosing ]
  The 24 hour post dose is optional depending on blood volume restrictions.
• Part 1: Pharmacodynamics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Urine cGMP [ Time Frame: Between 4 and 8 hours post dose ]
  A single urine sample will be collected between 4 to 8 hours post-dose.
• Part 2: Percentage of patients falling into each category based on global ranking [ Time Frame: Up to 52 weeks ]
  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

Current Secondary Outcome Measures (submitted: January 12, 2023)

• Part 1: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From first dose to 30 days after last dose of study drug in Part 1 ]
  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) [ Time Frame: From first dose to 30 days after last dose of study drug in Part 2 (up to 56 weeks) ]
  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 [ Time Frame: 52 weeks ]
  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 [ Time Frame: Baseline, Week 4, 12, 24, 36, and 52 ]
  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 [ Time Frame: Baseline, Week 4, 12, 24, 36, and 52 ]
  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) [ 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 ]
  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 [ 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 ]
  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) [ 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 ]
  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) [ 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 ]
  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) [ 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 ]
  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) [ 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 ]
  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) [ 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 ]
  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.

Original Secondary Outcome Measures (submitted: February 4, 2016)

• Part 2: Time to first occurrence of Category 1 or Category 2 event [ Time Frame: 52 weeks ]
  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 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
• Part 2: Change from baseline in NYHA/Ross functional class [ Time Frame: Baseline to 52 weeks ]
  NYHA/Ross functional class will be compared through 52 weeks of double-blind treatment
• Part 2: Change from baseline in Patient Global impression of severity score (PGIS) scale [ Time Frame: Baseline to 52 weeks ]
  PGIS scale will be compared for LCZ696 and enalapril through 52 weeks of double-blind treatment
• Part 2: Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Clearance from plasma in steady state (CL,ss) [ Time Frame: Week 2, 12, 52 ]
  The steady state population PK parameter clearance will be estimated to be used in model.
• Part 2: Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Volume of distribution in steady state [ Time Frame: Week 2, 12, 52 ]
  The steady state population PK parameter volume of distribution will be estimated to be used in model.
• Part 2: Population K of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Absorption rate constant in steady state (Ka,ss) [ Time Frame: Week 2, 12, 52 ]
  The steady state population PK parameter Ka will be estimated to be used in model.
• Part 2: 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) [ Time Frame: Week 2, 12, 52 ]
  The steady state population PK parameter T 1/2 will be estimated to be used in model.
• Part 2: Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Maximum drug concentration in plasma at steady state (Cmax,ss) [ Time Frame: Week 2, 12, 52 ]
  The steady state population PK parameter Cmax will be estimated to be used in model.
• Part 2: Population PK of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Lowest plasma concentration observed during a dosing interval at steady state (Cmin,ss) [ Time Frame: Week 2, 12, 52 ]
  The steady state population PK parameter Cmin will be estimated to be used in model.
• Part 2: 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) [ Time Frame: Week 2, 12, 52 ]
  The steady state population PK parameter AUC will be estimated to be used in model.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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

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

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
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Pediatric Heart Failure

Intervention

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

Study Arms

• 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.
  Interventions:

  • Drug: LCZ696
  • Drug: Enalapril
• 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.
  Interventions:

  • Drug: Enalapril
  • Drug: Placebo of LCZ696
• 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.
  Interventions:

  • Drug: LCZ696
  • Drug: Placebo of Enalapril
  • Drug: LCZ696

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 25, 2021): 393
• Original Estimated Enrollment (submitted: February 4, 2016): 360
• Actual Study Completion Date: January 3, 2022
• Actual Primary Completion Date: January 3, 2022 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Month to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Austria, Bulgaria, Canada, China, Croatia, Czechia, Finland, France, Germany, Hungary, India, Israel, Italy, Japan, Jordan, Korea, Republic of, Lebanon, Poland, Portugal, Russian Federation, Saudi Arabia, Singapore, Spain, Switzerland, Taiwan, Thailand, Turkey, United States
• Removed Location Countries: Puerto Rico, Romania, South Africa, Sweden

Administrative Information

• NCT Number: NCT02678312
• Other Study ID Numbers: CLCZ696B2319; 2015-004207-22 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: January 2023