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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02678312
Recruitment Status : Recruiting
First Posted : February 9, 2016
Last Update Posted : January 10, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE February 4, 2016
First Posted Date  ICMJE February 9, 2016
Last Update Posted Date January 10, 2020
Actual Study Start Date  ICMJE November 3, 2016
Estimated Primary Completion Date April 21, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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
Change History Complete list of historical versions of study NCT02678312 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE 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  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Pediatric Heart Failure
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 4, 2016)
360
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 21, 2021
Estimated Primary Completion Date April 21, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Month to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals +41613241111
Listed Location Countries  ICMJE India,   Argentina,   Austria,   Bulgaria,   Canada,   China,   Croatia,   Czechia,   Finland,   France,   Germany,   Hungary,   Israel,   Italy,   Japan,   Jordan,   Korea, Republic of,   Lebanon,   Poland,   Portugal,   Puerto Rico,   Romania,   Russian Federation,   Saudi Arabia,   Singapore,   South Africa,   Spain,   Sweden,   Switzerland,   Taiwan,   Thailand,   Turkey,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02678312
Other Study ID Numbers  ICMJE CLCZ696B2319
2015-004207-22 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novartis
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP