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

Novartis

Status and phase: Completed; Phase 3; Phase 2

Conditions: Pediatric Heart Failure

Treatments: Drug: Enalapril; Drug: Placebo of Enalapril; Drug: LCZ696; Drug: Placebo of LCZ696

Study type: Interventional

Funder types: Industry

Identifiers

NCT02678312

2015-004207-22 (EudraCT Number)

CLCZ696B2319

Details and patient eligibility

About

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.

Full 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.

Enrollment: 393 patients

Sex: All

Ages: 1 month to 17 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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393 participants in 3 patient groups

Part 1: LCZ696 open label

Experimental group

Description:

LCZ696 open label: For Age Groups 1 and 2, either 1) 0.8 mg/kg or 2) 3.1 mg/kg or both. For Age Group 3, either 1) 0.4 mg/kg or 2) 1.6 mg/kg or both. After LCZ696 PK assessment, patients will be maintained on open-label Enalapril provided locally by the study site, or standard of care also provided locally by the study site, for heart failure treatment, if patient intended to participate in Part 2.

Treatment:

Drug: LCZ696

Drug: LCZ696

Drug: Enalapril

Part 2: Enalapril

Active Comparator group

Description:

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). Administered in a double-blind fashion.

Treatment:

Drug: Enalapril

Drug: Placebo of LCZ696

Part 2: LCZ696

Experimental group

Description:

LCZ696 3.125 mg granules and adult formulation (50, 100, 200 mg) can be given based on patient weight. Administered in a double-blind fashion.

Treatment:

Drug: LCZ696

Drug: LCZ696

Drug: Placebo of Enalapril