LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction

Condition(s) targeted: Chronic Heart Failure

Intervention: LCZ696 (Drug); Valsartan (Drug); Placebo (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: Novartis Pharmaceuticals

Official(s) and/or principal investigator(s):
Novartis Pharmaceuticals, Study Director, Affiliation: Novartis Pharmaceuticals
Novartis, Study Director, Affiliation: Novartis

The study will assess the effects of 36 weeks of treatment with LCZ696 compared to valsartan on N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) in patients with chronic heart failure and preserved left-ventricular ejection fraction.

Official title: A 36-week, Randomized, Double-blind, Multi-center, Parallel Group, Active Controlled Study to Evaluate the Efficacy, Safety and Tolerability of LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)

Secondary outcome:

Change From Baseline in NT-proBNP and Brain Natriuretic Peptide (BNP)

Change From Baseline in Plasma Cyclic Guanine Monophosphate (cGMP)

Change From Baseline in Echocardiography (ECHO) Parameters: Left Ventricular End (LVE) Diastolic Diameter, LVE Systolic Diameter, Septal End Diastolic Thickness, Posterior LV Wall End Diastolic Thickness, Relative Wall Thickness, Left Atrial Dimension

Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume

Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction

Change From Baseline in Echocardiography Parameters: Left Ventricular Mass

Change From Baseline in Echocardiography Parameters: Left Ventricular Mass Index

Change From Baseline in Echocardiography Parameters: Left Atrial Volume Index

Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus

Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio

Change in Echocardiography Parameters: Isovolumic Relaxation Time

Change From Baseline in Echocardiography Parameters: Tricuspid Regurgitation Velocity

Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores

Percentage of Participants With Clinical Composite Assessment of Improved, Unchanged or Worsened

Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV

Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)

Change From Baseline in Serum Creatinine

Change From Baseline in Albumin/Creatinine Ratio

Change From Baseline in Arterial Stiffness Parameters: Brachial Systolic Blood Pressure (SBP), Brachial Diastolic Blood Pressure (DBP), Central Augmentation Pressure, Central Pressure at T1-DP, Central SBP, Central DBP, Central Mean Pressure

Change From Baseline in Arterial Stiffness Parameters: Heart Rate Correct Cen Aug/Pulse Ht

Change From Baseline in Arterial Stiffness Parameters: Heart Rate

Change From Baseline in Arterial Stiffness Parameters: Pulse Wave Velocity

Change From Baseline in Sitting SBP, Sitting DBP and Sitting Pulse Pressure (PP)

Minimum age: 40 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients with documented stable chronic heart failure (NYHA II-IV):

- LVEF ≥ 45% (local measurement, assessed by echocardiography, MUGA, CT scan, MRI

or ventricular angiography)

- the ejection fraction must have been obtained within 6 months prior to

randomization or after any MI or other event that would affect ejection fraction.

- Plasma NT-proBNP > 500 pg/ml at Visit 1.

- Patients with documented stable chronic heart failure (NYHA II-IV).

- Patients receiving ACE inhibitors (ACEi), an angiotensin receptor blockers (ARB)

and/or a beta blockers must be on a stable dose of these medications stable for the 1 month period prior to Visit 1.

- Patients must be on diuretic therapy prior to Visit 1 (flexible dosing is permitted).

- Patients with a controlled systolic BP, defined as a target systolic BP less than 140

mm Hg; participants with BP up to and including 160 mm Hg are eligible for enrollment if they are on three or more medications to control BP at randomization (Visit 2).

- Patients with at least one of the following symptoms at the time of screening (Visit

1):

- Dyspnea on exertion

- Orthopnea

- Paroxysmal nocturnal dyspnea

- Peripheral edema

- Patients must have an eGFR ≥ 30 ml/min/1. 73 m2 at Visit 1 (calculated by the

Modification of Diet in Renal Disease formula).

- Patients with a potassium ≤5. 2 mmol/l at Visit 1.

Exclusion Criteria:

- Patients with a prior LVEF reading <45%, at any time.

- Patients who require treatment with both an ACE inhibitor and an ARB.

- Isolated right heart failure due to pulmonary disease.

- Dyspnea and/or edema from non-cardiac causes, such as lung disease, anemia, or severe

obesity.

- Presence of hemodynamically significant mitral and /or aortic valve disease.

- Presence of hemodynamically significant obstructive lesions of left ventricular

outflow tract, including aortic stenosis.

- Presence of hypertrophic obstructive cardiomyopathy.

- Other protocol-defined inclusion/exclusion criteria may apply

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Related publications:

Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ; Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012 Oct 20;380(9851):1387-95. doi: 10.1016/S0140-6736(12)61227-6. Epub 2012 Aug 26.

Starting date: November 2009
Last updated: July 16, 2015