Chronic Heart Failure With Reduced Ejection Fraction
Conditions
Keywords
LCZ696, sacubitril/valsartan, VO2peak, heart failure, systolic heart failure, heart failure with reduced ejection fraction, exercise capacity
Brief summary
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.
Detailed description
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.
Interventions
DRUGLCZ696
LCZ696 100 mg bid for 2 weeks followed by LCZ696 200 mg bid for 10 weeks. Treatment was administered as oral tablets.
DRUGEnalapril
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.
DRUGPlacebo matching LCZ696
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.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with a diagnosis of chronic heart failure (NYHA class III) and reduced ejection fraction (LVEF ≤ 40%) * Reduced ability to exercise, evidenced by VO2peak ≤ 18 ml/min per kg * Patients had to be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks prior to the screening visit and until randomization visit.
Exclusion criteria
* History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs * Previous history of intolerance to recommended target doses of 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 * Impaired renal function * Pregnant or nursing (lactating) women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 3 Months of Treatment | Baseline, 3 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 6 Weeks of Treatment | Baseline, 6 weeks | 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. |
| Change From Baseline in the Minute Ventilation (VE) to Carbon Dioxide Output Slope (VE/VCO2 Slope) | Baseline, 6 weeks, 3 months | 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. |
| Change From Baseline in Exercise Capacity (Watt) at Ventilatory Anaerobic Threshold (VAT) | Baseline, 6 weeks, 3 months | 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. |
| Change From Baseline in Rate of Perceived Exertion (Perceived Dyspnea and Perceived Fatigue) During Exercise Assessed by Borg Scale | Baseline, 3 months | 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. |
Countries
Germany
Participant flow
Recruitment details
Participants took part in 34 investigative sites in Germany.
Pre-assignment details
Participants were randomized 1:1 to receive either LCZ696 or enalapril during the double-blind period.
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks. | 103 |
| Enalapril Enalapril 5 mg oral twice daily (bid) for 2 weeks followed by enalapril 10 mg oral bid for 10 weeks.
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. | 98 |
| Total | 201 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Non-compliance with study treatment | 0 | 1 |
| Overall Study | Subject/guardian decision | 1 | 0 |
| Overall Study | Withdrawal of informed consent | 0 | 1 |
Baseline characteristics
| Characteristic | LCZ696 | Enalapril | Total |
|---|---|---|---|
| Age, Continuous | 66.1 Years STANDARD_DEVIATION 10.792 | 67.6 Years STANDARD_DEVIATION 9.961 | 66.9 Years STANDARD_DEVIATION 10.396 |
| Race/Ethnicity, Customized Black | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucassian | 101 Participants | 96 Participants | 197 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 17 Participants | 21 Participants | 38 Participants |
| Sex: Female, Male Male | 86 Participants | 77 Participants | 163 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 103 | 1 / 98 |
| other Total, other adverse events | 52 / 103 | 36 / 98 |
| serious Total, serious adverse events | 12 / 103 | 14 / 98 |
Outcome results
Primary
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
Population: Full Analysis Set including patients with a valid measurements for the outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 | Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 3 Months of Treatment | 0.51 mL/kg/min | Standard Error 0.18 |
| Enalapril | Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 3 Months of Treatment | 0.19 mL/kg/min | Standard Error 0.188 |
p-value: 0.232795% CI: [-0.21, 0.85]ANCOVA
Secondary
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
Population: Full Analysis Set including patients with a valid measurements for the outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LCZ696 | Change From Baseline in Exercise Capacity (Watt) at Ventilatory Anaerobic Threshold (VAT) | 6 weeks | 1.71 Watt | Standard Error 1.168 |
| LCZ696 | Change From Baseline in Exercise Capacity (Watt) at Ventilatory Anaerobic Threshold (VAT) | 3 months | 2.45 Watt | Standard Error 1.436 |
| Enalapril | Change From Baseline in Exercise Capacity (Watt) at Ventilatory Anaerobic Threshold (VAT) | 6 weeks | 0.83 Watt | Standard Error 1.234 |
| Enalapril | Change From Baseline in Exercise Capacity (Watt) at Ventilatory Anaerobic Threshold (VAT) | 3 months | -0.83 Watt | Standard Error 1.483 |
Comparison: 6 weeksp-value: 0.618195% CI: [-2.58, 4.32]ANCOVA
Comparison: 3 monthsp-value: 0.125495% CI: [-0.93, 7.48]ANCOVA
Secondary
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
Population: Full Analysis Set including patients with a valid measurements for the outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 | Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 6 Weeks of Treatment | 0.28 mL/kg/min | Standard Error 0.185 |
| Enalapril | Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 6 Weeks of Treatment | 0.42 mL/kg/min | Standard Error 0.195 |
p-value: 0.624795% CI: [-0.68, 0.41]ANCOVA
Secondary
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
Population: Full Analysis Set including patients with a valid measurements for the outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LCZ696 | Change From Baseline in Rate of Perceived Exertion (Perceived Dyspnea and Perceived Fatigue) During Exercise Assessed by Borg Scale | Borg value perceived dyspnea | -0.19 Score on scale | Standard Error 0.212 |
| LCZ696 | Change From Baseline in Rate of Perceived Exertion (Perceived Dyspnea and Perceived Fatigue) During Exercise Assessed by Borg Scale | Borg value perceived fatigue | -0.04 Score on scale | Standard Error 0.167 |
| Enalapril | Change From Baseline in Rate of Perceived Exertion (Perceived Dyspnea and Perceived Fatigue) During Exercise Assessed by Borg Scale | Borg value perceived fatigue | -0.20 Score on scale | Standard Error 0.178 |
| Enalapril | Change From Baseline in Rate of Perceived Exertion (Perceived Dyspnea and Perceived Fatigue) During Exercise Assessed by Borg Scale | Borg value perceived dyspnea | 0.11 Score on scale | Standard Error 0.223 |
Comparison: Borg value dyspneap-value: 0.343295% CI: [-0.93, 0.33]ANCOVA
Comparison: Borg value fatiguep-value: 0.531995% CI: [-0.34, 0.65]ANCOVA
Secondary
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.
Time frame: Baseline, 6 weeks, 3 months
Population: Full Analysis Set including patients with a valid measurements for the outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LCZ696 | Change From Baseline in the Minute Ventilation (VE) to Carbon Dioxide Output Slope (VE/VCO2 Slope) | 6 weeks | -1.05 no units | Standard Error 0.597 |
| LCZ696 | Change From Baseline in the Minute Ventilation (VE) to Carbon Dioxide Output Slope (VE/VCO2 Slope) | 3 months | 0.76 no units | Standard Error 0.542 |
| Enalapril | Change From Baseline in the Minute Ventilation (VE) to Carbon Dioxide Output Slope (VE/VCO2 Slope) | 6 weeks | 0.18 no units | Standard Error 0.629 |
| Enalapril | Change From Baseline in the Minute Ventilation (VE) to Carbon Dioxide Output Slope (VE/VCO2 Slope) | 3 months | -0.07 no units | Standard Error 0.575 |
Comparison: 6 weeksp-value: 0.167895% CI: [-2.98, 0.52]ANCOVA
Comparison: 3 monthsp-value: 0.305295% CI: [-0.77, 2.43]ANCOVA