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

• ClinicalTrials.gov Identifier: NCT02678312
• Recruitment Status: Active, not recruiting
• First Posted: February 9, 2016
• Last Update Posted: March 26, 2021
• 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
• Last Update Posted Date: March 26, 2021
• Actual Study Start Date: November 3, 2016
• Estimated Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 14, 2016)

• Part 1: Pharmacokinetics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Maximum drug concentration in plasma (Cmax) [ Time Frame: 0 (pre-dose), 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 (pre-dose), 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 (pre-dose), 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 (pre-dose), 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 (pre-dose), 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 (pre-dose) and 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 (pre-dose), 4 and, 8 hours post dosing ]
• Part 1: Pharmacodynamics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Urine cGMP [ Time Frame: 0 (pre-dose) hour and between 4 and 8 hours post dose ]
  One urine sample at 0 hr (predose) and another urine sample between 4 to 8 hours post-dose will be collected.
• Part 1: Pharmacodynamics of LCZ696 analytes (sacubitril, LBQ657, and valsartan): Plasma B-type natriuretic peptide (BNP) [ Time Frame: 0 (pre-dose), 4 and 8 hour 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

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: October 14, 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 PK 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.

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 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 consist of two parts (Part 1 and Part 2). The purpose of Part 1 is to evaluate the way the body absorbs, distributes and removes the drug LCZ696. This will help determine the proper dose of LCZ696 for Part 2 of the study.

The purpose for Part 2 is to compare the effectiveness and safety of LCZ696 with enalapril in pediatric heart failure patients over 52 weeks of treatment.

• Detailed Description: Not Provided
• 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), 50 mg, 100 mg, 200 mg dosage strengths
• Drug: Enalapril
  Enalapril will be open label in Part 1 and double blind in Part 2
• Drug: Placebo of LCZ696
• Drug: Placebo of Enalapril

Study Arms

• Experimental: Part 1: LCZ696 open label
  LCZ696 open label either 1) 0.8 mg/kg or 2) 3.1 mg/kg or both. After LCZ696 PK assessment, patients will be maintained on open-label Enalapril or standard of care for heart failure treatment, if patient consents 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).
  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.
  Interventions:

  • Drug: LCZ696
  • Drug: Placebo of Enalapril

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 25, 2021): 393
• Original Estimated Enrollment (submitted: February 4, 2016): 360
• Estimated Study Completion Date: January 7, 2022
• Estimated Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

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, South Africa, Spain, Switzerland, Taiwan, Thailand, Turkey, United States
• Removed Location Countries: Puerto Rico, Romania, 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: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: March 2021