pediatric patients with heart failure due to systemic left ventricle systolic dysfunction.

Primary Objective:  Part 1: The primary objective is to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of LCZ696 in pediatric HF patients  Part 2: The primary objective is to determine whether LCZ696 is superior to enalapril for treatment of heart failure as assessed using a global rank endpoint in pediatric HF patients Secondary Objectives:  Part 1: To assess the safety and tolerability of LCZ696 in pediatric patients with HF  Part 2: To determine whether LCZ696 is superior to enalapril in delaying time to first occurrence of the composite of either Category 1 or 2 events (e.g. death, worsening HF)  Part 2: To determine whether LCZ696 is superior to enalapril for improving NYHA (New York Heart Association)/Ross functional class  Part 2: To determine whether LCZ696 is superior to enalapril for improving the Patient Global Impression of Severity (PGIS) score  Part 2: To characterize the population PK of LCZ696 exposure in pediatric patients with HF  Part 2: To assess the safety and tolerability of LCZ696 compared to enalapril in pediatric patients with HF

LCZ696

Sacubitril/Valsartan as Sacubitril Valsartan sodium salt complex

film-coated tablet/capsule

film-coated tablet 50mg、100mg、200mg；/capsule 12.5mg、31.25mg

1. Primary endpoint(s):
Part 1: PK and PD of LCZ696 after single dose treatment
Part 2: Global Rank endpoint through 52 weeks of treatment
2. Secondary endpoints:
Part 1: Safety and tolerability including AEs, laboratory, vital signs of LCZ696 in Part 1
Part 2: Time to first occurrence of Category 1 or Category 2 event through 52 weeks of treatment
Part 2: NYHA/Ross functional class change from baseline through 52 weeks of treatment
Part 2: PGIS score change from baseline through 52 weeks of treatment
Part 2: Population PK LCZ696
Part 2: Safety and tolerability including AEs, laboratory, ECG, vital signs data through 52 weeks
of double-blind treatment
3. Exploratory endpoints:
Part 2: PedsQL score change from baseline through 52 weeks of treatment
Part 2: NTproBNP change from baseline through 12 and 52 weeks of treatment
Part 2: PGIC score through 52 weeks of treatment

Inclusion criteria:
Patients eligible for inclusion in this study (Part 1 and Part 2) must fulfill all of the following criteria:
1. Written informed consent by parent(s)/legal guardian(s) for the pediatric patient must be obtained
before any study-specific assessment is performed.* A consent or assent may also be required for
some patients depending upon their age and local requirement.
2. Male or female, inpatient or outpatient, 1 month (≥44 weeks post-conception for pre-term infants)
to < 18 years of age.
3. Chronic heart failure resulting from left ventricular systolic dysfunction, and receiving chronic HF
therapy (if not newly diagnosed). [Note: the study will target enrollment of 25% ACEI/ARB naïve
patients for Part 2 only].
4. NYHA classification II-IV (older children: 6 to less than 18 year old) or Ross HF classification IIIV (younger children: less than 6 year old) any time prior to screening. [Note: the patient may
NYHA or Ross class I at time of screening if there is a prior history of NYHA or Ross II-IV].
5. Systemic left ventricular ejection fraction (EF) ≤ 40% or fractional shortening ≤20% (assessed by
echocardiogram, MRI, MUGA or left ventricular angiogram within 1 month before patient begins
Part 1 or Part 2).
6. Biventricular physiology with systemic left ventricle.
7. For Part 1 PK/PD, patients must be treated with an ACEI or ARB prior to screening. For Part 1
PK/PD, 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 single dose assessment. (Group 3 patients only
participate in the LCZ696 0.8 mg/kg and not the second LCZ696 3.1 mg/kg PK/PD assessment)
8. HF etiologies include: Congenital Cardiac Malformation with systemic ventricular systolic
dysfunction; Idiopathic Cardiomyopathy; Familial/Inherited and/or Genetic Cardiomyopathy;
History of Myocarditis; Neuromuscular Disorder; Inborn Error of Metabolism; Mitochondrial
Disorder; Acquired (Chemotherapy, Iatrogenic, Infection, Rheumatic, Nutritional); Ischemic (e.g.
Kawasaki Disease, post-operative); Left ventricular noncompaction
*Assessments of HF (e.g. ECHO) in patients that are done according to current local
institutional/hospital standard protocol or that are part of routine clinical care can be used to support
patient screening and may have taken place before signing informed consent. An informed consent
must be obtained from a patient once they become 18 years old during the study

Exclusion criteria:
Patients fulfilling any of the following criteria are not eligible for inclusion in this study (Part 1 and
Part 2). No additional exclusions may be applied by the Investigator, in order to ensure that the study
population will be representative of all eligible patients.
1. Patients with single ventricle or systemic right ventricle
2. Patients listed for heart transplantation as United Network for Organ Sharing (UNOS) Status 1A
or hospitalized waiting for transplant while on inotropes or with ventricular assist device at time of
entry into the study
3. Sustained or symptomatic dysrhythmias uncontrolled with drug or device therapy
4. 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.
5. Patients with unoperated obstructive or severe regurgitant valvular (aortic, pulmonary, or
tricuspid) disease, or significant systemic ventricular outflow obstruction or aortic arch obstruction
6. Patients with restrictive or hypertrophic cardiomyopathy
7. Active myocarditis (diagnosed with presumed or acute myocarditis within 3 months of enrollment)
8. Symptomatic hypotension or blood pressures (BPs) below the calculated 5th percentile systolic BP
(SBP) for age at screening visit
9. Renal vascular hypertension (including renal artery stenosis)
10. Severe pulmonary hypertension (defined by pulmonary vascular resistance (PVR) index >6 Wood
units-m
2
) unresponsive to vasodilator agents (such as oxygen, nitroprusside or nitric oxide). Note
measurement of PVR is not a requirement for study eligibility
11. History or current clinical evidence of moderate-to severe obstructive pulmonary disease or
reactive airway diseases (e.g. asthma)
12. Serum potassium >5.3 mmol/L at Visit 1 or at Visit 301
13. Patients with significant renal (eGFR calculated using the modified Schwartz formula < 30%
mean GFR for age); hepatic (serum aspartate aminotransferase or alanine aminotransferase > 3
times upper limit of normal); gastrointestinal or biliary disorders (that could impair absorption,
metabolism, or excretion of orally administered medications)
14. Concurrent terminal illness or other severe disease (e.g. acute lymphocytic leukemia) or other
significant laboratory values that, in the opinion of the Investigator, precludes study participation
or survival
15. Patients with a history of angioedema
16. Patients with allergy or hypersensitivity to ACEI or ARB
17. Patients who have parents or legal guardians who do not give consent or allow the child to give
assent, or inability of the patient or the parents/legal guardians to follow instructions or comply
with follow-up procedures
18. Pregnant or nursing (lactating) women
19. Women of child-bearing potential, defined as all women physiologically capable of becoming
pregnant, unless they are using basic methods of contraception during dosing of investigational
drug. Basic contraception methods include:
 Total abstinence (when this is in line with the preferred and usual lifestyle of the subject and if
acceptable by the local regulation). Periodic abstinence (e.g. calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
contraception
 Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy),
total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In
case of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level assessment
 Male sterilization (at least 6 months prior to screening). For female subjects on the study, the
vasectomized male partner should be the sole partner for that subject
 Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault
caps). For UK: with spermicidal foam/gel/film/cream/ vaginal suppository
 Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of
contraception or other forms of hormonal contraception that have comparable efficacy (failure
rate <1%); for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS)
 In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking investigational drug
20. Use of other investigational drugs within 5 half-lives or within 30 days of enrollment, whichever is
shorter
21. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar
chemical classes
22. Any major solid organ transplant recipient
23. History of malignancy of any organ system, treated or untreated, within the past year with a life
expectancy less than 1 year
24. Any advanced severe or unstable disease that may interfere with the primary or secondary study
outcome evaluations or put the patient at special risk
25. Any other medical conditions that may put the patient at risk or influence study results in the
Investigator’s opinion, or that the Investigator deems unsuitable for the study