CTRI/2017/09/009732.

Study name	A 24‐week, randomized, double‐blind, multi‐center, parallel group, active controlled study to evaluate the effect of LCZ696 on NT‐proBNP, symptoms, exercise function and safety compared to individualized medical management of comorbidities in patients with heart failure and preserved ejection fraction
Methods	Study design: parallel RCT Anticipated completion date: February 2020
Participants	Estimated enrolment: 2200 Inclusion criteria: Written informed consent must be obtained before any assessment is performed. LVEF? 45% by echocardiography performed at site within 6 months prior to Visit 1 or during the screening epoch. Symptom(s) of HF requiring treatment with diuretic(s) (including loop or thiazide diuretics, or mineralocorticoid antagonist (MRAs) for at least 30 days prior to Visit 1. Current symptom(s) of HF (NYHA class II‐IV) at Visit 1 Structural heart disease demonstrated by echocardiographic evidence of left atrial enlargement (LAE) or left ventricular hypertrophy (LVH) as defined below (any local measurement made during the screening epoch or within the 6 months prior to Visit 1): LAE defined by at least one of the following: LA width (diameter) ? 3.8 cm or LA length ? 5.0 cm or LA area ? 20 cm2 or LA volume ? 55 mL or LA volume index? 29 mL/m2 LVH defined by septal thickness or posterior wall thickness?1.1 cm Receiving evidence based therapy for comorbidities as determined by the individual clinical profile of the patient (eg age and number and type of comorbidities) with stable doses for the previous four weeks NT‐proBNP > 220 pg/mL for patients with no atrial fibrillation/atrial flutter (AF) or > 600 pg/mL for patients with AF on the Visit 1 electrocardiogram (ECG) KCCQ CSS 9. Patients on angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy must have a history of HTN Exclusion criteria: Any prior echocardiographic measurement of LVEF Acute coronary syndrome (including myocardial infarction [MI]),cardiac surgery, other major cardiovascular (CV) surgery, or urgent percutaneous coronary intervention (PCI) within the 3 months prior to Visit 1 or an elective PCI within 30 days prior to Visit 1. 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% and LVEF? 45% by the time screening. Current acute decompensated HF requiring augmented therapy with diuretics, vasodilators and/or inotropic drugs. Current use of renin inhibitor(s). History of hypersensitivity to LCZ696 or its components. Patients with a known history of angioedema Walking distance primarily limited by non‐cardiac comorbid conditions. Probable alternative diagnoses that in the opinion of the investigator could account for the patient’s HF symptoms (ie dyspnea, fatigue) such as significant pulmonary disease (including primary pulmonary HTN), anemia or obesity. Specifically, patients with the following are excluded: a. severe pulmonary disease including chronic obstructive pulmonary disease (COPD) (ie requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy or hospitalized for pulmonary decompensation within 12 months) or b. hemoglobin (Hgb) or c. body mass index (BMI) > 40 kg/m2 Patients with any of the following: a. systolic blood pressure (SBP) ? 180 mmHg at Visit 1, or b. SBP > 150 mmHg and patient is receiving 3 or more antihypertensive drugs. Antihypertensive drugs include, but are not limited to, a thiazide or other diuretic, MRA, ACEi, ARB, beta blocker and calcium channel blocker (CCB), or c. SBP Patients with HbA1c > 7.5% not treated for diabetes Patients with history of any dilated cardiomyopathy, including peripartum cardiomyopathy, chemotherapy induced cardiomyopathy, or viral myocarditis. Evidence of right sided HF in the absence of left‐sided structural heart disease Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy. Clinically significant congenital heart disease that could be the cause of the patient’s symptoms and signs of HF. Presence of hemodynamically significant valvular heart disease in the opinion of the investigator. Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within the 3 months prior to Visit 1. Coronary or carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention during the trial. Life‐threatening or uncontrolled arrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate > 110 beats per minute (bpm). Patients with a cardiac resynchronization therapy (CRT) device. Patients with prior major organ transplant or intent to transplant(ie on transplant list)
Interventions	LCZ696 versus enalapril versus valsartan (of interest to this review is comparison LCZ696 versus valsartan) 24 weeks
Outcomes	NT‐proBNP; quality of life;
Starting date	15 June 2017
Contact information	Murugananthan K: murugananthan.k@novartis.com
Notes