Clinical trial NCT02678312: Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LCZ696 Followed by a 52-week, Double-blind Study of LCZ696 Compared With Enalapril in Pediatric Patients With Heart Failure
Official title: Multicenter, Open-label Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LCZ696 Followed by a 52-week Randomized, Double-blind, Parallel Group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696 Compared With Enalapril in Pediatric Patients From 1 Month to < 18 Years of Age With Heart Failure Due to Systemic Left Ventricle Systolic Dysfunction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Pediatric Heart Failure
Keywords: Pediatric Heart failure,
systemic left ventricle,
reduced ejection fraction
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-02-09
Enrollment: 393
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Maximum Drug Concentration in Plasma (Cmax)
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
measure: Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Time to Maximum Plasma Concentration (Tmax)
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
measure: Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)
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
measure: 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)
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
measure: Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, and Valsartan): Clearance From Plasma (CL/F)
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
measure: Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril): Time Required to Drug Concentration to Decrease by Half (T 1/2)
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
measure: Part 1: Pharmacodynamics (PD) of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma B-type Natriuretic Peptide (BNP)
timeFrame: Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2
measure: Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma N-terminal Pro-brain Natriuretic Peptide (NTproBNP)
timeFrame: Baseline (0 hrs pre dose) and optional 24 hrs post dosing on Day 1 of Period 1 and Period 2
measure: Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma Cyclic Guanosine Monophosphate (cGMP)
timeFrame: Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2
measure: Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Urine cGMP
timeFrame: Baseline (0 hrs pre dose), 4 to 8 hrs post dose on Day 1 of Period 1 and Period 2
measure: Part 2: Percentage of Participants With Worst Event in Each Category Based on Global Ranking
timeFrame: Up to 52 weeks
Secondary outcomes:
measure: Part 1: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first dose to 30 days after last dose of study drug in Part 1
measure: Part 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first dose to 30 days after last dose of study drug in Part 2 (up to 56 weeks)
measure: Part 2: Exposure-adjusted Incidence Rate of Category 1 or Category 2 Event
timeFrame: 52 weeks
measure: Part 2: Percentage of Participants With Change From Baseline in New York Heart Association (NYHA)/Ross Functional Class
timeFrame: Baseline, Week 4, 12, 24, 36, and 52
measure: Part 2: Percentage of Participants With Change From Baseline in Patient Global Impression of Severity (PGIS) Score
timeFrame: Baseline, Week 4, 12, 24, 36, and 52
measure: Part 1 and Part 2: Population PK of LCZ696 Analytes: Clearance From Plasma (CL)
timeFrame: 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
measure: Part 1 and Part 2: Population PK of LCZ696 Analytes: Volume of Distribution in Steady State
timeFrame: 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
measure: Part 1 and Part 2: Population PK of LCZ696 Analytes: Absorption Rate Constant (Ka)
timeFrame: 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
measure: Part 1 and Part 2: Population PK of LCZ696 Analytes: Time Required to Drug Concentration to Decrease by Half (T 1/2)
timeFrame: 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
measure: Part 1 and Part 2: Population PK of LCZ696 Analytes: Maximum Drug Concentration in Plasma at Steady State (Cmax,ss)
timeFrame: 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
measure: Part 1 and Part 2: Population PK of LCZ696 Analytes: Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss)
timeFrame: 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
measure: 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)
timeFrame: 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
Other outcomes:
Locations:
city: Loma Linda
country: United States
facility: Novartis Investigative Site
state: California
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: Palo Alto
country: United States
facility: Novartis Investigative Site
state: California
city: San Diego
country: United States
facility: Novartis Investigative Site
state: California
city: Aurora
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Gainesville
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Saint Petersburg
country: United States
facility: Novartis Investigative Site
state: Florida
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Indianapolis
country: United States
facility: Novartis Investigative Site
state: Indiana
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Minneapolis
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Rochester
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Saint Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Charlotte
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Cleveland
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Salt Lake City
country: United States
facility: Novartis Investigative Site
state: Utah
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Ramos Mejia
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad de Salta
country: Argentina
facility: Novartis Investigative Site
state: Provincia De Salta
city: Innsbruck
country: Austria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Beijing
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Zagreb
country: Croatia
facility: Novartis Investigative Site
city: Praha 5
country: Czechia
facility: Novartis Investigative Site
city: Helsinki
country: Finland
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Pessac
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
state: Delhi
city: New Delhi
country: India
facility: Novartis Investigative Site
state: Delhi
city: Ahmedabad
country: India
facility: Novartis Investigative Site
state: Gujarat
city: Kochi
country: India
facility: Novartis Investigative Site
state: Kerala
city: Be'er-Sheva
country: Israel
facility: Novartis Investigative Site
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Obu
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Sapporo city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Omura
country: Japan
facility: Novartis Investigative Site
state: Nagasaki
city: Bunkyo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Setagaya-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinjuku ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Toyama-city
country: Japan
facility: Novartis Investigative Site
state: Toyama
city: Saitama
country: Japan
facility: Novartis Investigative Site
city: Amman
country: Jordan
facility: Novartis Investigative Site
state: JOR
city: Yangsan
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeongsangnam Do
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: El Achrafîyé
country: Lebanon
facility: Novartis Investigative Site
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Carnaxide
country: Portugal
facility: Novartis Investigative Site
state: Lisboa
city: Coimbra
country: Portugal
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Riyadh
country: Saudi Arabia
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Cordoba
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Lausanne
country: Switzerland
facility: Novartis Investigative Site
city: Kaohsiung City
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Bangkoknoi
country: Thailand
facility: Novartis Investigative Site
state: Bangkok
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Konak
country: Turkey
facility: Novartis Investigative Site
Study officials:
References: