Exercise Capacity Study of LCZ696 vs. Enalapril in Patients With Chronic Heart Failure and Reduced Ejection Fraction.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02768298
• Collaborator: (none)
• Enrollment: 201
• Locations: 34
• Arms: 2
• Actual Duration (Months): 40.4
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Heart Failure With Reduced Ejection Fraction	Drug: LCZ696; Drug: Enalapril; Drug: Placebo matching enalapril; Drug: Placebo matching LCZ696	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 201 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Active-controlled Study to Assess the Effect of LCZ696 Compared With Enalapril to Improve Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF).
• Actual Study Start Date: Jul 12, 2016
• Actual Primary Completion Date: Nov 25, 2019
• Actual Study Completion Date: Nov 25, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.	Drug: LCZ696; LCZ696 100 mg bid for 2 weeks followed by LCZ696 200 mg bid for 10 weeks. Treatment was administered as oral tablets.; Drug: Placebo matching enalapril; 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.
Active Comparator: 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.	Drug: Enalapril; 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.; Drug: Placebo 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Regensburg	Bavaria	Germany	93053
2	Novartis Investigative Site	Dresden	Sachsen	Germany	01099
3	Novartis Investigative Site	Berlin		Germany	10787
4	Novartis Investigative Site	Berlin		Germany	13055
5	Novartis Investigative Site	Berlin		Germany	13353
6	Novartis Investigative Site	Berlin		Germany	13405
7	Novartis Investigative Site	Bonn		Germany	53115
8	Novartis Investigative Site	Dresden		Germany	01277
9	Novartis Investigative Site	Dresden		Germany	01307
10	Novartis Investigative Site	Erfurt		Germany	99089
11	Novartis Investigative Site	Frankfurt		Germany	60389
12	Novartis Investigative Site	Freiburg		Germany	79106
13	Novartis Investigative Site	Gottingen		Germany	37075
14	Novartis Investigative Site	Hamburg		Germany	22291
15	Novartis Investigative Site	Heidelberg		Germany	69115
16	Novartis Investigative Site	Kiel		Germany	24105
17	Novartis Investigative Site	Koblenz		Germany	56068
18	Novartis Investigative Site	Koeln-Nippes		Germany	50733
19	Novartis Investigative Site	Koeln		Germany	50937
20	Novartis Investigative Site	Koeln		Germany	51065
21	Novartis Investigative Site	Leverkusen		Germany	51375
22	Novartis Investigative Site	Ludwigsburg		Germany	71634
23	Novartis Investigative Site	Ludwigshafen		Germany	67063
24	Novartis Investigative Site	Muenchen		Germany	81675
25	Novartis Investigative Site	Neuwied		Germany	56564
26	Novartis Investigative Site	Nienburg		Germany	31582
27	Novartis Investigative Site	Rotenburg an der Fulda		Germany	36199
28	Novartis Investigative Site	Rüdersdorf		Germany	15562
29	Novartis Investigative Site	Siegen		Germany	57072
30	Novartis Investigative Site	Ulm		Germany	89077
31	Novartis Investigative Site	Villingen-Schwenningen		Germany	78052
32	Novartis Investigative Site	Worms		Germany	67550
33	Novartis Investigative Site	Wuerzburg		Germany	97080
34	Novartis Investigative Site	Wuppertal		Germany	42117

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 24, 2019
• Statistical Analysis Plan - Feb 10, 2020

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02768298
• Other Study ID Numbers: CLCZ696BDE01; 2015-004632-35
• First Posted: May 11, 2016
• Last Update Posted: Oct 8, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: LCZ696; sacubitril/valsartan; VO2peak; heart failure; systolic heart failure; heart failure with reduced ejection fraction; exercise capacity
• Additional relevant MeSH terms: Heart Failure; Enalapril; Enalaprilat; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	Participants took part in 34 investigative sites in Germany.
Pre-assignment Detail	Participants were randomized 1:1 to receive either LCZ696 or enalapril during the double-blind period.

Arm/Group Title	LCZ696	Enalapril
Arm/Group Description	LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.	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.
Period Title: Overall Study
STARTED	103	98
COMPLETED	99	91
NOT COMPLETED	4	7

Baseline Characteristics

Arm/Group Title	LCZ696	Enalapril	Total
Arm/Group Description	LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.	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.	Total of all reporting groups
Overall Participants	103	98	201
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	66.1 (10.792)	67.6 (9.961)	66.9 (10.396)
Sex: Female, Male (Count of Participants)
Female	17 16.5%	21 21.4%	38 18.9%
Male	86 83.5%	77 78.6%	163 81.1%
Race/Ethnicity, Customized (Count of Participants)
Caucassian	101 98.1%	96 98%	197 98%
Black	0 0%	1 1%	1 0.5%
Other	2 1.9%	1 1%	3 1.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 3 Months of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set including patients with a valid measurements for the outcome measure.

Arm/Group Title	LCZ696	Enalapril
Arm/Group Description	LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.	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.
Measure Participants	98	90
Least Squares Mean (Standard Error) [mL/kg/min]	0.51 (0.180)	0.19 (0.188)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Enalapril
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2327
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean
	Estimated Value	0.32
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.268
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Peak Respiratory Oxygen Uptake (VO2peak) Adjusted to Body Weight) After 6 Weeks of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set including patients with a valid measurements for the outcome measure.

Arm/Group Title	LCZ696	Enalapril
Arm/Group Description	LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.	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.
Measure Participants	97	88
Least Squares Mean (Standard Error) [mL/kg/min]	0.28 (0.185)	0.42 (0.195)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Enalapril
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6247
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.68 to 0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.277
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in the Minute Ventilation (VE) to Carbon Dioxide Output Slope (VE/VCO2 Slope)
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set including patients with a valid measurements for the outcome measure.

Arm/Group Title	LCZ696	Enalapril
Arm/Group Description	LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.	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.
Measure Participants	103	98
6 weeks	-1.05 (0.597)	0.18 (0.629)
3 months	0.76 (0.542)	-0.07 (0.575)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Enalapril
	Comments	6 weeks
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1678
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.23
	Confidence Interval	(2-Sided) 95%; -2.98 to 0.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.888
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Enalapril
	Comments	3 months
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3052
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; -0.77 to 2.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.809
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Exercise Capacity (Watt) at Ventilatory Anaerobic Threshold (VAT)
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set including patients with a valid measurements for the outcome measure.

Arm/Group Title	LCZ696	Enalapril
Arm/Group Description	LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.	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.
Measure Participants	103	98
6 weeks	1.71 (1.168)	0.83 (1.234)
3 months	2.45 (1.436)	-0.83 (1.483)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Enalapril
	Comments	6 weeks
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6181
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; -2.58 to 4.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.744
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Enalapril
	Comments	3 months
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1254
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	3.28
	Confidence Interval	(2-Sided) 95%; -0.93 to 7.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.124
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Rate of Perceived Exertion (Perceived Dyspnea and Perceived Fatigue) During Exercise Assessed by Borg Scale
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set including patients with a valid measurements for the outcome measure.

Arm/Group Title	LCZ696	Enalapril
Arm/Group Description	LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.	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.
Measure Participants	103	98
Borg value perceived dyspnea	-0.19 (0.212)	0.11 (0.223)
Borg value perceived fatigue	-0.04 (0.167)	-0.20 (0.178)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Enalapril
	Comments	Borg value dyspnea
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3432
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.93 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.317
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Enalapril
	Comments	Borg value fatigue
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5319
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.251
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days (16 weeks on average).
Adverse Event Reporting Description	Any signs or symptoms that occurs during study treatment plus the 30 days post treatment.
Arm/Group Title	LCZ696		Enalapril
Arm/Group Description	LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks.		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.
All Cause Mortality
	LCZ696		Enalapril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/103 (1.9%)		1/98 (1%)
Serious Adverse Events
	LCZ696		Enalapril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/103 (11.7%)		14/98 (14.3%)
Cardiac disorders
Acute myocardial infarction	1/103 (1%)		0/98 (0%)
Angina pectoris	1/103 (1%)		0/98 (0%)
Aortic valve incompetence	1/103 (1%)		0/98 (0%)
Atrial fibrillation	2/103 (1.9%)		1/98 (1%)
Atrial flutter	0/103 (0%)		1/98 (1%)
Atrial tachycardia	0/103 (0%)		1/98 (1%)
Atrial thrombosis	0/103 (0%)		1/98 (1%)
Bradycardia	0/103 (0%)		1/98 (1%)
Cardiac failure	1/103 (1%)		2/98 (2%)
Cardiogenic shock	0/103 (0%)		1/98 (1%)
Coronary artery disease	1/103 (1%)		0/98 (0%)
Tachycardia	1/103 (1%)		0/98 (0%)
Ventricular tachycardia	2/103 (1.9%)		0/98 (0%)
Gastrointestinal disorders
Pancreatitis	0/103 (0%)		1/98 (1%)
General disorders
Non-cardiac chest pain	0/103 (0%)		1/98 (1%)
Vascular stent occlusion	0/103 (0%)		1/98 (1%)
Infections and infestations
Appendicitis	1/103 (1%)		0/98 (0%)
Gastroenteritis norovirus	1/103 (1%)		0/98 (0%)
Pneumonia	2/103 (1.9%)		0/98 (0%)
Septic shock	1/103 (1%)		0/98 (0%)
Injury, poisoning and procedural complications
Contusion	0/103 (0%)		1/98 (1%)
Investigations
Angiocardiogram	0/103 (0%)		1/98 (1%)
International normalised ratio abnormal	1/103 (1%)		0/98 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Glioblastoma	0/103 (0%)		1/98 (1%)
Nervous system disorders
Seizure	0/103 (0%)		1/98 (1%)
Syncope	0/103 (0%)		2/98 (2%)
Renal and urinary disorders
Renal failure	0/103 (0%)		1/98 (1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/103 (1%)		1/98 (1%)
Pleural effusion	0/103 (0%)		1/98 (1%)
Vascular disorders
Hypotension	1/103 (1%)		0/98 (0%)
Other (Not Including Serious) Adverse Events
	LCZ696		Enalapril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/103 (50.5%)		36/98 (36.7%)
General disorders
Fatigue	2/103 (1.9%)		7/98 (7.1%)
Infections and infestations
Nasopharyngitis	9/103 (8.7%)		3/98 (3.1%)
Metabolism and nutrition disorders
Hyperkalaemia	9/103 (8.7%)		3/98 (3.1%)
Nervous system disorders
Dizziness	14/103 (13.6%)		6/98 (6.1%)
Respiratory, thoracic and mediastinal disorders
Cough	3/103 (2.9%)		9/98 (9.2%)
Dyspnoea	2/103 (1.9%)		6/98 (6.1%)
Vascular disorders
Hypotension	27/103 (26.2%)		11/98 (11.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. Novartis does not prohibit any investigator from publishing. Any publications from a single site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.