The purpose of the study was to determine the effect of LCZ696 vs. enalapril on improvement of exercise capacity in patients with chronic heart failure with reduced ejection fraction.
This study was a randomized, double-blind, double-dummy, parallel-group, active-controlled, two-arm trial to compare LCZ696 200 mg twice daily (bid) to enalapril 10 mg bid in improving exercise capacity, daily physical activity and quality of life in patients with stable chronic heart failure (New York Heart Association III) and reduced left ventricular ejection fraction (LVEF ≤ 40%). The study consisted of a screening period of 2 weeks during which the subject's eligibility for the study was assessed followed by a double blind treatment period of 12 weeks. Eligible subjects were randomized 1:1 to receive either LCZ696 or enalapril during the double-blind period. Treatment was initiated with LCZ696 100 mg bid or enalapril 5 mg bid (enalapril 10 mg bid for patients at a stable daily dose of enalapril above 10 mg per day or corresponding doses of other angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) prior first screening visit), respectively. Dose was up-titrated after 2 weeks to the final dose of LCZ696 200 mg bid or enalapril 10 mg bid. Patients continued to take their background medications for chronic heart failure during the study, with the exception of ACEI or ARBs which were replaced by investigational treatment and had to be discontinued before first dose of study drug. The primary objective was to demonstrate the superiority of LCZ696 200 mg bid compared to enalapril 10 mg bid in improving exercise tolerance (peak respiratory oxygen uptake (VO2peak), adjusted to body weight) as assessed by cardio-pulmonary-exercise testing (CPET) in patients with stable chronic heart failure (NYHA III) and reduced ejection fraction (LVEF ≤ 40%) after 3 months treatment.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
201
LCZ696 100 mg bid for 2 weeks followed by LCZ696 200 mg bid for 10 weeks. Treatment was administered as oral tablets.
Enalapril 5 mg bid for 2 weeks followed by enalapril 10 mg bid for 10 weeks. Treatment was administered as oral tablets. Patients who prior Screening were at a stable daily dose of enalapril above 10 mg per day (or corresponding doses of other ACEI/ARB) started the study at a dose of enalapril 10 mg bid.
Patients randomized to LCZ696 arm also received placebo matching enalapril (enalapril 0 mg tablets) to ensure the blinding during the entire course of the study.
Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 3 Months of Treatment
Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. One of the parameters attained by this test is the peak respiratory oxygen uptake (VO2peak). CPET to assess VO2peak was performed at a cycle ergometer at baseline (Visit 2, 9 days prior randomization) and after 6 weeks and 3 months of treatment (Visit 6 and Visit 7, respectively). The VO2peak adjusted to body weight was calculated based on the corresponding visit's VO2peak (unadjusted) and body weight data by using the following formula: VO2peak (unadjusted)/body weight. Higher values of VO2peak indicate less symptom severity and therefore a positive change from baseline indicates improvement.
Time frame: Baseline, 3 months
Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 6 Weeks of Treatment
Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. One of the parameters attained by this test is the peak respiratory oxygen uptake (VO2peak). CPET to assess VO2peak was performed at a cycle ergometer at baseline (Visit 2, 9 days prior randomization) and after 6 weeks and 3 months of treatment (Visit 6 and Visit 7, respectively). The VO2peak adjusted to body weight was calculated based on the corresponding visit's VO2peak (unadjusted) and body weight data by using the following formula: VO2peak (unadjusted)/body weight. A positive change from baseline indicates less symptom severity.
Time frame: Baseline, 6 weeks
Change From Baseline in the Minute Ventilation (VE) to Carbon Dioxide Output Slope (VE/VCO2 Slope)
Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. One of the parameters attained by this test is the minute ventilation (VE) to carbon dioxide output slope (VE/VCO2 slope). High values of VE/VCO2 slope resembles the inability to eliminate CO2 by respiration (inefficient ventilation). A negative change from baseline indicates less symptom severity.
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Patients randomized to enalapril arm also received placebo matching LCZ696 (LCZ696 0 mg tablets) to ensure the blinding during the entire course of the study.
Novartis Investigative Site
Regensburg, Bavaria, Germany
Novartis Investigative Site
Dresden, Saxony, Germany
Novartis Investigative Site
Berlin, Germany
Novartis Investigative Site
Berlin, Germany
Novartis Investigative Site
Berlin, Germany
Novartis Investigative Site
Berlin, Germany
Novartis Investigative Site
Bonn, Germany
Novartis Investigative Site
Cologne, Germany
Novartis Investigative Site
Cologne, Germany
Novartis Investigative Site
Dresden, Germany
...and 24 more locations
Time frame: Baseline, 6 weeks, 3 months
Change From Baseline in Exercise Capacity (Watt) at Ventilatory Anaerobic Threshold (VAT)
Cardiopulmonary exercise testing (CPET) is an established method to evaluate the exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the measurement of respiratory gases during physical (exercise) stress. CPET was performed at a cycle ergometer with a workload that started at 10 watts (W) and then increased by 10W for each 1-minute stage. Exercise capacity assessed as workload in watts was determined at the ventilatory anaerobic threshold (VAT) which represents the transition from aerobic to partially anaerobic glucose metabolism in muscle, leading to increasing carbon dioxide exhalation in comparison to oxygen uptake. A positive change from baseline in exercise capacity (watt) indicates improvement.
Time frame: Baseline, 6 weeks, 3 months
Change From Baseline in Rate of Perceived Exertion (Perceived Dyspnea and Perceived Fatigue) During Exercise Assessed by Borg Scale
The individually perceived exertion, in terms of perceived dyspnea and perceived fatigue, during cardiopulmonary exercise testing (CPET) was assessed by Borg scale which is a 15 point scale, starting from 6 which indicates "No exertion at all" to 20 which means "Maximal exertion". Change in Borg scale for both perceived dyspnea and perceived fatigue were measured at different time points at Baseline (Visit 2, 9 days prior randomization) and 3 months of treatment (Visit 7). Maximum value among the time points at every visit was used for the analysis. A negative change from baseline in Borg value of perceived dyspnea and perceived fatigue indicates improvement.
Time frame: Baseline, 3 months