A Randomized, Double-blind Controlled Study Comparing LCZ696 to Medical Therapy for Comorbidities in HFpEF Patients (PARALLAX)

Novartis

Status and phase: Completed; Phase 3

Conditions: Heart Failure With Preserved Ejection Fraction

Treatments: Drug: sacubitril/valsartan; Drug: Placebo to match enalapril; Drug: Enalapril; Drug: Placebo to match valsartan; Drug: Placebo to match sacubitril/valsartan; Drug: Valsartan

Study type: Interventional

Funder types: Industry

Identifiers

NCT03066804

CLCZ696D2302

2016-003410-28 (EudraCT Number)

Details and patient eligibility

About

The purpose of this study is to demonstrate the superiority of LCZ696 over individualized medical therapy for comorbidities in reducing N-terminal pro-brain natriuretic peptide (NT-proBNP) and improving exercise capacity and HF symptoms in patients with heart failure with preserved ejection fraction (HFpEF).

Full description

This study was a 24-week, randomized, double-blind, multi-center, parallel group, active controlled study to evaluate sacubitril/valsartan compared to individualized medical therapy on NT proBNP, exercise capacity, symptoms and QoL in patients with heart failure and preserved left ventricular ejection (HFpEF) fraction (LVEF > 40%). Patients were initially stratified into one of three strata according to prior treatment for comorbidities: Angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or no prior renin angiotensin system inhibitors (RASi). Patients in each stratum were randomized in a 1:1 ratio and received either sacubitril/valsartan or comparator (i.e.

enalapril for patients in ACEi strata, valsartan for patients in the ARB strata and placebo for patients in the No RASi strata). There was no designated proportion of patients planned in each stratum; the strata were populated based upon the patient's prior treatment regimen. The study consisted of a screening epoch of up to 2 weeks and a randomized treatment epoch of 24 weeks, which included a 1 to 4 week study drug up-titration epoch followed by a 20 to 23 week maintenance epoch. Uptitration to target doses was recommended to occur within the first four weeks of the study, and was performed by Investigator's discretion based on the patient's clinical status.

Enrollment: 2,572 patients

Sex: All

Ages: 45+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Left ventricular ejection fraction (LVEF) >40% by echo within 6 months prior to study entry or during the screening epoch
• Symptom(s) of heart failure (HF) requiring treatment with diuretics (including loop, or thiazide diuretics, or mineralocorticoid antagonist [MRAs]) for at least 30 days prior to study entry
• NYHA class II-IV
• Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.
• NT-proBNP > 220 pg/mL for patients with no atrial fibrillation/atrial flutter (AF) or >600 pg/mL for patients with AF
• KCCQ clinical summary score < 75
• Patients on ACEi or ARB therapy must have a history of HTN

Exclusion criteria

• Any prior measurement of LVEF ≤ 40%, under stable conditions
• Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months , or urgent percutaneous coronary intervention (PCI) within 3 months or an elective PCI within 30 days prior to study entry
• Any clinical event within the 6 months prior to Visit 1 that could have reduced the LVEF (eg MI, coronary artery bypass graft [CABG]), unless an echo measurement was performed after the event confirming the LVEF to be >40%
• Current (within 30 days from Visit 1) acute decompensated HF requiring therapy.
• Current (within 30 days from Visit 1) use of renin inhibitor(s), dual RAS blockade or LCZ696
• History of hypersensitivity to LCZ696 or its components
• Patients with a known history of angioedema
• Walk distance primarily limited by non-cardiac comorbid conditions at study entry
• Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dL males and < 9.5 g/dL females, or body mass index (BMI) > 40 kg/m^2.
• Systolic blood pressure (SBP) ≥ 180 mmHg at study entry, or SBP >150 mmHg and <180 mmHg at study entry unless the patient is receiving 3 or more antihypertensive drugs, or SBP < 110 mmHg at study entry.
• Patients with HbA1c > 7.5% not treated for diabetes
• Patients with prior major organ transplant or intent to transplant (ie on transplant list)
• eGFR < 30 ml/min/1.73 m^2 as measured by MDRD at screening
• Serum potassium > 5.2 mmol /L (or equivalent plasma potassium value) at study entry
• History or presence of any other disease with a life expectancy of < 3 years
• Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception

Other protocol-defined inclusion/exclusion criteria may apply.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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2,572 participants in 2 patient groups

sacubitril/valsartan (LCZ696)

Experimental group

Description:

All patients who fulfill the inclusion/exclusion criteria will be stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients in the ACEi strata will receive LCZ696 or enalapril. Patients in the ARB strata will receive LCZ696 or valsartan. Patients in the no RASi strata will receive LCZ696 or matching placebo. Patients in the ACEi and ARB strata will take two pills twice daily for each dose: one tablet from the LCZ696 pack and one tablet from the comparator pack. Patients in the no RASi strata will take only one tablet twice daily (LCZ696 or matching placebo). In the LCZ696 arm, patients will receive active LCZ696 in titrated doses from level 1 up to level 3 (50 mg, 100 mg and 200 mg twice daily orally).

Treatment:

Drug: Placebo to match enalapril

Drug: Placebo to match valsartan

Drug: sacubitril/valsartan

Comparator

Active Comparator group

Description:

Patients randomized to the comparator arm will receive either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum). Patients in the ACE stratum randomized to comparator, will receive enalapril in titrated doses from level 1 up to level 3 (2.5 mg, 5 mg and 10 mg twice daily). Patients in the ARB stratum randomized to comparator will receive valsartan in titrated doses from level 1 up to level 3 (40 mg , 80 mg and 160 mg twice daily). Patients in the no RASi stratum randomized to comparator will receive LCZ696 matching placebo.

Treatment:

Drug: Placebo to match sacubitril/valsartan

Drug: Valsartan

Drug: Enalapril