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

Study Overview
=================
Brief Summary
-----------------
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

Conditions
-----------------
Chronic Heart Failure

Intervention / Treatment
-----------------
* Drug: LCZ696
* Drug: Valsartan
* Drug: Placebo


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCZ696<br>During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid. | Drug: LCZ696<br>* 50 mg, 100 mg and 200 mg tablets<br>Drug: Placebo<br>* matching placebo to LCZ696 and Valsartan<br>|
| Active Comparator: Valsartan<br>During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid. | Drug: Valsartan<br>* 40 mg, 80 mg and 160 mg tablets<br>Drug: Placebo<br>* matching placebo to LCZ696 and Valsartan<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | Evaluation of NT-proBNP was performed by a central laboratory. Change from baseline in NT-proBNP was presented as a ratio where the ratio was calculated as the NT-proBNP value at 12 weeks over the NT-proBNP value at baseline. A ratio < 1 indicates improvement. | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in NT-proBNP and Brain Natriuretic Peptide (BNP) | Evaluation of NT-proBNP and BNP was performed by a central laboratory. Change from baseline in NT-proBNP and in BNP was presented as a ratio where the ratio for NT-proBNP was calculated as the NT-proBNP value at 36 weeks over the NT-proBNP value at baseline, and the ratio for BNP was calculated as the BNP value at 36 weeks over the BNP value at baseline. A ratio < 1 indicates improvement. | baseline, 36 weeks | 
| Change From Baseline in Plasma Cyclic Guanine Monophosphate (cGMP) | Evaluation of cGMP was performed by a central laboratory. Change from baseline in cGMP was presented as a ratio where the ratio was calculated as the cGMP value at 36 weeks over the cGMP value at baseline. A ratio < 1 indicates improvement. | baseline, 36 weeks | 
| 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 | A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline, 36 weeks | 
| Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume | A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline, 36 weeks | 
| Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction | A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline, 36 weeks | 
| Change From Baseline in Echocardiography Parameters: Left Ventricular Mass | A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline, 36 weeks | 
| Change From Baseline in Echocardiography Parameters: Left Ventricular Mass Index | A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline, 36 weeks | 
| Change From Baseline in Echocardiography Parameters: Left Atrial Volume Index | A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline, 36 weeks | 
| Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus | A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline, 36 weeks | 
| Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio | A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A ratio < 1 indicates improvement. | Baseline, 36 weeks | 
| Change in Echocardiography Parameters: Isovolumic Relaxation Time | A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline, 36 weeks | 
| Change From Baseline in Echocardiography Parameters: Tricuspid Regurgitation Velocity | A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline, 36 weeks | 
| Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores | The KCCQ is a self-administered questionnaire. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and quality of life, each with different Likert scale wording, including limitations, frequency, bother, change in condition, understanding, levels of enjoyment and satisfaction. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A positive change from baseline indicates improvement. | baseline, 36 weeks | 
| Percentage of Participants With Clinical Composite Assessment of Improved, Unchanged or Worsened | The clinical composite assessment is defined as follows: Improved = a) participant improved (markedly or moderately) in the global assessment of disease activity with no worsening of NYHA functional class and no major adverse cardiovascular event or b) participant improved in NYHA functional class with no worsening (markedly or moderately) in the global assessment of disease activity and no major adverse cardiovascular event. Worsened = participant worsened (markedly or moderately) in the global assessment of disease activity or in NYHA functional class or experienced a major adverse cardiovascular event. Unchanged = participant does not meet the definition for improved or worsened. | 36 weeks | 
| Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV | The NYHA Functional Classification classifies patients' heart failure according to the severity of their symptoms. The classification is as follows: Class I: no limitation of physical activity, ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath); Class II: slight limitation to physical activity, comfortable at rest, ordinary physical activity results in fatigue, palpitation or dyspnea; Class III: marked limitation of physical activity, comfortable at rest, less than ordinary activity causes fatigue, palpitation or dyspnea; Class IV: unable to carry on any physical activity without discomfort, symptoms of heart failure at rest, if any physical activity is undertaken, discomfort increases. | baseline, 36 weeks | 
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | eGFR was calculated from the serum creatinine concentration determined by central laboratory assessment. A positive change from baseline indicates improvement. | baseline, 36 weeks | 
| Change From Baseline in Serum Creatinine | Evaluation of serum creatinine was performed by central laboratory. A negative change from baseline indicates improvement. | baseline, 36 weeks | 
| Change From Baseline in Albumin/Creatinine Ratio | Evaluation of albumin/creatinine was performed by central laboratory. A ratio < 1 indicates improvement. | baseline, 36 weeks | 
| 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 | A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement. | baseline, 36 weeks | 
| Change From Baseline in Arterial Stiffness Parameters: Heart Rate Correct Cen Aug/Pulse Ht | A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement. | baseline, 36 weeks | 
| Change From Baseline in Arterial Stiffness Parameters: Heart Rate | A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement. | baseline, 36 weeks | 
| Change From Baseline in Arterial Stiffness Parameters: Pulse Wave Velocity | A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement. | baseline, 36 weeks | 
| Change From Baseline in Sitting SBP, Sitting DBP and Sitting Pulse Pressure (PP) | Sitting blood pressure and sitting pulse pressure were assessed. A negative change from baseline indicates improvement. | baseline, 36 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic heart failure, preserved ejection fraction, cardiovascular disease, NT-proBNP, biomarkers, Heart failure with preserved left-ventricular ejection, fraction