|Principal Investigator: Ashwin Lal|
|Keywords: Device , Transcatheter , Ostium , Secundum||Department: Department of Pediatrics|
|IRB Number: 00090806|
|Specialty: Pediatric Cardiology|
|Recruitment Status: Recruiting|
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 to enalapril in pediatric patients from 1 month to < 18 years of age with heart failure due to systemic left ventricle systolic dysfunction.
The purpose of this study is to determine whether pediatric heart failure (HF) patients (1 month to < 18 years old) will derive greater clinical treatment benefit with LCZ696 compared to enalapril over 52 weeks treatment duration. This study includes two parts: Part 1 will determine the dose for Part 2. Part 2 will assess the efficacy and safety of LCZ696 compared to enalapril.
- The primary objective is to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of LCZ696 in pediatric HF patients.
- The primary objective is to determine whether LCZ696 is superior to enalapril for the treatment of heart failure as assessed using a global rank endpoint in pediatric HF patients.
- To assess the safety and tolerability of LCZ696 in pediatric patients with HF.
- 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).
- To determine whether LCZ696 is superior to enalapril for improving NYHA (New York Heart Association)/Ross functional class. To determine whether LCZ696 is superior to enalapril for improving the Patient Global Impression of Severity (PGIS) score.
- To characterize the population PK of LCZ696 exposure in pediatric patients with HF, including an assessment of steady-state sparse PK data in a subset of Group 2 patients.
- To assess the safety and tolerability of LCZ696 compared to enalapril in pediatric patients with HF
1. Male or female, inpatient or outpatient, 1 month to < 18 years of age.
2. Chronic heart failure resulting from left ventricular systolic dysfunction, and receiving chronic HF therapy (if not newly diagnosed).
3. NYHA classification II-IV (older children: 6 to less than 18 years old) or Ross HF classification II-IV (younger children: less than 6 years old) any time prior to screening.
4. Systemic left ventricular ejection fraction (EF) ≤ 45% or fractional shortening ≤22.5% (assessed by echocardiography, MRI, MUGA or left ventricular angiogram within 1 month before patient begin Part 2.
5. Biventricular physiology with systemic left ventricle.
6. For Part 1 PK/PD only, 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 a daily dose equivalent of at least enalapril 0.2 mg/kg prior to the LCZ696 3.1 mg/kg single dose assessment. For Part 1 PK/PD, patients in Group 3 must be currently treated with a daily dose equivalent of at least 0.1 mg/kg prior to the LCZ696 1.6 mg/kg single dose assessment.
7. Heart Failure 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 heart failure (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 take place before signing informed consent.
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 a transplant while on inotropes or with ventricular assist device at the time of entry into the study.
3. Sustained or symptomatic dysrhythmias uncontrolled with drug or device therapy.
4. For Part 2 only, 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
6. Patients with restrictive or hypertrophic cardiomyopathy.
7. For Part 2 only, 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 the screening visit and as described in Appendix 4 (p 130).
9. Renal vascular hypertension (including renal artery stenosis).
10. Severe pulmonary hypertension (defined by, pulmonary vascular resistance (PVR) index >6 Wood units-m2) 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 GRF for age, Appendix 10, Table 22-1, p 174); 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 diseases (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 history of angioedema.
16. Patients with allergy or hypersensitivity to ACEI/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 highly effective methods of contraception
during dosing of investigational drug and for 7 days after study drug discontinuation.
Highly effective 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.
- Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%); for example hormone vaginal ring or transdermal hormone contraception.
- 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
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.
26. Patient breastfed by a mother taking ACEI.