Study of Efficacy and Safety of LCZ696 in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction

The purpose of this study was to assess the effect of LCZ696 at a target dose of 200 mg b.i.d. compared to enalapril 10 mg b.i.d., in addition to the background heart failure (HF) treatment, on delaying time to first occurrence of either cardiovascular (CV) death or HF hospitalization events in Japanese patients with stable chronic heart failure (CHF), New York Heart Association (NYHA) classes II-IV and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 35%).

The study consisted of two parts: the core part and the Open label extension (OLE) epoch.

The core part of this study was a multicenter, randomized, double-blind, double-dummy, parallel-group, active-controlled study to assess the effect of LCZ696 at a target dose of 200 mg b.i.d. and enalapril 10 mg b.i.d. on CV mortality and morbidity reduction in Japanese HF patients with reduced ejection fraction. Patients who met the eligibility criteria at screening entered a 2 week, single-blind, active treatment run-in epoch in which they received LCZ696 50 mg b.i.d. Patients who tolerated LCZ696 50 mg b.i.d. for 2 weeks were randomized in a 1:1 ratio to receive LCZ696 100 mg b.i.d. or enalapril 5 mg b.i.d. for 4 weeks during the double-blind treatment epoch. The patient randomization was stratified by using NT-proBNP measured at the screening visit as a stratification factor. The patients were then titrated up to the target dose of LCZ696 200 mg b.i.d. or enalapril 10 mg b.i.d. if they tolerated 4 weeks treatment of LCZ696 100 mg b.i.d. or enalapril 5 mg b.i.d. Dose adjustment (LCZ696 50-100 mg b.i.d. \& enalapril 2.5-5 mg b.i.d.) was permitted if not tolerated at the target dose of study drugs during the double-blind treatment epoch.

This was an event-driven study in which subjects remained on the study (regardless of whether receiving investigational medications) until the projected number of patients with primary events (approximately 57 events) had been reached.

The Open label extension (OLE) epoch was conducted following the completion of the core part, with the aim to provide access to LCZ696 for eligible subjects until the marketed product was available in Japan or 2 years from the date of the first subject enrolled in the OLE epoch, whichever occurred first, and also to obtain the safety and tolerability data of long-term treatment with LCZ696.

Upon completion of the core part, the eligibility of the subjects to enter the OLE epoch was assessed by the investigator at OLE baseline (Visit 301), which occurred on the same day as the end of study (EOS) visit of the core part (Visit 299). At this visit, subjects were switched to open-label LCZ696.

At Visit 302 (2 to 4 weeks after Visit 301), subjects who tolerated the open-label LCZ696 and met the safety monitoring criteria were up-titrated to the next higher level of daily dose. Thereafter, subject visits occurred at 8 weeks, and then every 4 months until EOS visit for OLE epoch.

Eligibility Criteria:
Inclusion Criteria:

* Written informed consent must be obtained before any assessment is performed.
* Outpatients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction:
* LVEF ≤ 35% at Visit 1 (any local measurement, made within the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular angiography is also acceptable, provided no subsequent measurement above 35%)
* NT-proBNP ≥ 600 pg/ml at Visit 1 OR NT-proBNP ≥ 400 pg/ml at Visit 1 and a hospitalization for HF within the last 12 months (according to central laboratory measurements)
* Patients must be on an ACEI or an ARB at a stable dose for at least 4 weeks before Visit 1.
* Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1 (reason should be documented if patients reported contraindications or intolerance).
* An aldosterone antagonist should also be considered in all patients, taking account of renal function, serum potassium and tolerability. If given, the dose of aldosterone antagonist should be optimized according to guideline recommendations and patient tolerability, and should be stable for at least 4 weeks prior to Visit 1. Other evidence-based therapy for HF should also be considered e.g. cardiac resynchronization therapy and an implantable cardioverter-defibrillator in selected patients, as recommended by guidelines.

Exclusion Criteria:

* History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes, ACEIs, ARBs, NEP inhibitors as well as known or suspected contraindications to the study drugs.
* Previous documented history of intolerance to ACEIs or ARBs.
* Known history of angioedema.
* Requirement of treatment with both ACEIs and ARBs.
* Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy).
* Symptomatic hypotension and/or a SBP \< 100 mmHg at screening or \< 95 mmHg at the end of run-in.
* Estimated GFR \< 30 mL/min/1.73 m2 as measured by the Japanese formula at screening, or the end of run-in or \> 35% decline in eGFR between screening and end of run-in (according to local measurements).
* Serum potassium \> 5.2 mmol/L (mEq/L) at screening or \> 5.4 mmol/L (mEq/L) at the end of run-in (according to local measurements).
* Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1.
* Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1.
* Symptomatic bradycardia or second (except asymptomatic Wenckebach block) or third degree heart block without a pacemaker.
* Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation.
* Presence of other hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis.
* Presence of bilateral renal artery stenosis.