Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF)

Novartis

Status and phase: Completed; Phase 3

Conditions: Heart Failure With Preserved Ejection Fraction

Treatments: Drug: LCZ696; Drug: Valsartan

Study type: Interventional

Funder types: Industry

Identifiers

NCT01920711

2013-001747-31 (EudraCT Number)

CLCZ696D2301

Details and patient eligibility

About

The purpose of this study was to evaluate the effect of LCZ696 compared to valsartan in the reduction of cardiovascular death and heart failure(HF) hospitalizations in patients with HF with preserved ejection fraction.

Full description

This was a multicenter, randomized, double-blind, parallel group, active-controlled, study to evaluate the efficacy and safety of sacubitril/valsartan compared to valsartan, on morbidity and mortality in heart failure patients (NYHA Class II-IV) with preserved ejection fraction. Specifically, the study evaluated the effect of sacubitril/valsartan compared to the active comparator valsartan in the reduction of the rate of CV death and total HF hospitalizations in patients with HFpEF. The trial consisted of two periods: (1) a single-blind treatment run-in epoch that lasted from 3 to 8 weeks, in which patients received valsartan 80 mg bid, followed by sacubitril/valsartan 100 mg bid and (2) a double-blind randomized treatment epoch (sacubitril/valsartan 200 mg bid or valsartan 160 mg bid). In this study, investigators were responsible for assessing and submitting all events which could potentially fulfill the criteria for the primary, secondary, or other clinical endpoints to a Clinical Endpoint Committee (CEC). Investigator reported events were assessed by the CEC for adjudication.

For angioedema or angioedema-like events, investigators completed an Adjudication Questionnaire for an Angioedema-like Event form. All angioedema reports were forwarded to an Angioedema Adjudication Committee (AAC) by Novartis for assessment.

Enrollment: 4,822 patients

Sex: All

Ages: 50+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Left ventricular ejection fraction (LVEF) ≥45% by echo during screening epoch or within 6 months prior to study entry.
• Symptom(s) of heart failure (HF) and requiring treatment with diuretic(s) for HF at least 30 days prior to study entry.
• Current symptom(s) of HF (NYHA class II-IV)
• Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.
• Elevated NT-proBNP

Exclusion criteria

• Any prior measurement of LVEF < 40%.
• Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months , or urgent percutaneous coronary intervention within 3 months or and elective PCI within 30 days prior to entry.
• Any clinical event within the 6 months prior to entry could have reduced the LVEF (e.g., MI, CABG), unless an echo measurement performed after the event confirms a LVEF ≥45%.
• Current acute decompensated HF requiring therapy.
• Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB) or a renin inhibitor.
• Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dl, or body mass index (BMI) > 40 kg/m2.
• Systolic blood pressure (SBP) ≥ 180 mmHg at entry, or SBP >150 mmHg and <180 mmHg at entry unless the patient is receiving 3 or more antihypertensive drugs, or SBP < 110 mmHg at entry.

Other protocol-defined inclusion/exclusion criteria may apply.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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4,822 participants in 2 patient groups

LCZ696

Experimental group

Description:

Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of LCZ696 during the double blind period is 200 mg b.i.d.

Treatment:

Drug: LCZ696

Valsartan

Active Comparator group

Description:

Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of Valsartan during the double blind period is 160 mg b.i.d.

Treatment:

Drug: Valsartan