Trial Outcomes & Findings for randOmized stUdy Using acceleromeTry to Compare Sacubitril/valsarTan and Enalapril in Patients With Heart Failure (NCT NCT02900378)

Last Updated: 2020-09-02

Results Overview

The impact of LCZ696 (Sacubitril/Valsartan) and Enalapril on functional exercise capacity was measured by the Six Minute Walk Test at 12 weeks. The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

621 participants

Primary outcome timeframe

Baseline, Week 12

Results posted on

2020-09-02

Participant Flow

This study was conducted at 120 centers in 19 countries worldwide (Belgium, Bulgaria, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Iceland, Ireland, Latvia, Lithuania, Netherlands, Norway, Poland, Spain, Sweden and UK).

It was planned to recruit 300 patients per treatment arm, i.e. 600 patients in total. A total of 764 patients were screened, of whom 621 patients were randomized (310 in the sacubitril/valsartan group and 311 in the enalapril group).

Participant milestones

Participant milestones
Measure	LCZ696 (Sacubitril/Valsartan) LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Randomization (Visit 2) STARTED	310	311
Randomization (Visit 2) COMPLETED	287	283
Randomization (Visit 2) NOT COMPLETED	23	28
Treatment Phase STARTED	309	310
Treatment Phase Full Analysis Set	302	302
Treatment Phase COMPLETED	309	310
Treatment Phase NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	LCZ696 (Sacubitril/Valsartan) LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Randomization (Visit 2) Adverse Event	14	11
Randomization (Visit 2) Death	1	4
Randomization (Visit 2) Lost to Follow-up	1	0
Randomization (Visit 2) Non-compliance with Study Drug	1	1
Randomization (Visit 2) Protocol Deviation	1	7
Randomization (Visit 2) Withdrawal by Parent/Guardian	5	3
Randomization (Visit 2) Withdrawal of Informed Consent	0	2

Baseline Characteristics

The Demographic and Baseline Characteristics were done in the Safety Analysis Set.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LCZ696 (Sacubitril/Valsartan) n=310 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=311 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.	Total n=621 Participants Total of all reporting groups
Age, Continuous	67.16 Years STANDARD_DEVIATION 11.04 • n=309 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	66.62 Years STANDARD_DEVIATION 10.45 • n=310 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	66.89 Years STANDARD_DEVIATION 10.74 • n=619 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.
Sex: Female, Male Female	71 Participants n=309 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	61 Participants n=310 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	132 Participants n=619 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.
Sex: Female, Male Male	238 Participants n=309 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	249 Participants n=310 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	487 Participants n=619 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.
Race/Ethnicity, Customized Black or African American	1 Participants n=309 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	0 Participants n=310 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	1 Participants n=619 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.
Race/Ethnicity, Customized White	298 Participants n=309 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	299 Participants n=310 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	597 Participants n=619 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.
Race/Ethnicity, Customized Missing	10 Participants n=309 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	11 Participants n=310 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.	21 Participants n=619 Participants • The Demographic and Baseline Characteristics were done in the Safety Analysis Set.

PRIMARY outcome

Timeframe: Baseline, Week 12

Population: The Full Analysis Set (FAS) and FAS population subset without AE/SAE were considered

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12) Baseline (FAS)	365.37 meters Standard Deviation 108.18	371.08 meters Standard Deviation 104.41
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12) Week 12 (FAS)	395.80 meters Standard Deviation 113.11	395.33 meters Standard Deviation 105.94
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12) Change from BL at Week 12 (FAS)	31.57 meters Standard Deviation 67.35	24.89 meters Standard Deviation 51.64
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12) Baseline (FAS without AE/SAE)	364.72 meters Standard Deviation 106.86	371.18 meters Standard Deviation 105.13
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12) Week 12 (FAS without AE/SAE)	399.31 meters Standard Deviation 110.54	396.02 meters Standard Deviation 106.39
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12) Change from BL at Week 12 (FAS without AE/SAE)	35.75 meters Standard Deviation 58.76	25.87 meters Standard Deviation 51.73

PRIMARY outcome

Timeframe: Baseline, Week 12

Population: The FAS population with Multiple Imputation (MI), with Last Observation Carried Forward (LOCF) and without MI/LOCF were considered.

Non-sedentary physical activity is defined as \>= 178.50 activity counts per minute; the average number of minutes per day spent in non-sedentary physical activity is being calculated over 14 days before randomization (baseline i.e. week -2 to week 0) and the last 14 days of treatment (i.e. week 10 to week 12).

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) Baseline (FAS with MI)	510.11 minutes Standard Deviation 128.08	506.81 minutes Standard Deviation 139.60
Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) Week 12 (FAS with MI)	479.69 minutes Standard Deviation 124.23	487.53 minutes Standard Deviation 126.84
Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) Change from BL at Week 12 (FAS with MI)	-30.42 minutes Standard Deviation 102.55	-19.28 minutes Standard Deviation 104.04
Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) Baseline (FAS with LOCF)	512.07 minutes Standard Deviation 126.37	505.31 minutes Standard Deviation 129.74
Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) Week 12 (FAS with LOCF)	489.43 minutes Standard Deviation 127.36	490.09 minutes Standard Deviation 127.82
Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) Change from BL at Week 12 (FAS with LOCF)	-21.88 minutes Standard Deviation 68.55	-15.41 minutes Standard Deviation 74.45
Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) Baseline (FAS without MI/LOCF)	512.07 minutes Standard Deviation 126.37	505.31 minutes Standard Deviation 129.74
Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) Week 12 (FAS without MI/LOCF)	479.81 minutes Standard Deviation 122.45	486.85 minutes Standard Deviation 128.70
Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) Change from BL at Week 12 (FAS without MI/LOCF)	-25.14 minutes Standard Deviation 69.11	-20.51 minutes Standard Deviation 72.52

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: The Full Analysis Set (FAS) was considered.

The proportion of patients with improved performance (\>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS No	142 Participants	153 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS Yes	149 Participants	129 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS Missing	11 Participants	20 Participants

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: The Full Analysis Set (FAS) population subset without AE/SAE was considered.

The proportion of patients with improved performance (\>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=290 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=294 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS Subset Without AE/SAE No	133 Participants	146 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS Subset Without AE/SAE Yes	149 Participants	129 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS Subset Without AE/SAE Missing	8 Participants	19 Participants

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: The Full Analysis Set (FAS) was considered for patients with Baseline 6MWT equal to or less than 300 meters.

The proportion of patients with improved performance (\>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group in a subset of patients with baseline six-minute walk distance equal to or less than 300 meters.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=78 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=65 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS No	35 Participants	31 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS Yes	41 Participants	29 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS Missing	2 Participants	5 Participants

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: The Full Analysis Set (FAS) population subset without AE/SAE was considered for patients with Baseline 6MWT equal to or less than 300 meters.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=75 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=63 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS Subset Without AE/SAE No	33 Participants	30 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS Subset Without AE/SAE Yes	41 Participants	29 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS Subset Without AE/SAE Missing	1 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: The Full Analysis Set (FAS) was considered for patients with Baseline 6MWT between 100 or above and less than 450 meters.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=238 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=238 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS No	109 Participants	121 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS Yes	122 Participants	105 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS Missing	7 Participants	12 Participants

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: The Full Analysis Set (FAS) population subset without AE/SAE was considered for patients with Baseline 6MWT between 100 or above and less than 450 meters.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=230 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=231 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS Subset Without AE/SAE No	103 Participants	115 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS Subset Without AE/SAE Yes	122 Participants	105 Participants
Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS Subset Without AE/SAE Missing	5 Participants	11 Participants

SECONDARY outcome

Timeframe: Baseline, Week 4 and Week 8

Population: The Full Analysis Set (FAS) and FAS population subset without AE/SAE were considered.

The impact of LCZ696 (Sacubitril/Valsartan) and Enalapril on functional exercise capacity was measured by the Six Minute Walk Test at Weeks 4 and 8. The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 Change from BL at Week 4 (FAS)	19.13 meters Standard Deviation 49.16	13.72 meters Standard Deviation 51.39
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 Baseline (FAS without AE/SAE)	364.72 meters Standard Deviation 106.86	371.18 meters Standard Deviation 105.13
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 Change from BL at Week 4 (FAS without AE/SAE)	18.91 meters Standard Deviation 49.63	14.45 meters Standard Deviation 51.48
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 Baseline (FAS)	365.37 meters Standard Deviation 108.18	371.08 meters Standard Deviation 104.41
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 Week 4 (FAS)	385.22 meters Standard Deviation 110.55	385.02 meters Standard Deviation 109.92
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 Week 8 (FAS)	395.28 meters Standard Deviation 112.05	391.72 meters Standard Deviation 108.99
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 Change from BL at Week 8 (FAS)	28.72 meters Standard Deviation 57.99	21.15 meters Standard Deviation 52.75
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 Week 4 (FAS without AE/SAE)	384.58 meters Standard Deviation 107.69	385.92 meters Standard Deviation 110.81
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 Week 8 (FAS without AE/SAE)	396.64 meters Standard Deviation 110.65	391.82 meters Standard Deviation 109.72
Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 Change from BL at Week 8 (FAS without AE/SAE)	30.38 meters Standard Deviation 57.07	21.51 meters Standard Deviation 52.99

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: The Full Analysis Set was considered

Non-sedentary physical activity is defined as \>= 178.50 activity counts per minute; the average number of minutes per day spent in non-sedentary physical activity will be calculated over 14 days before randomization (baseline) and the last 14 days of treatment (i.e week 10 to week 12)

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Number and Percentage of Participants Who Show Increased Levels (>= 10% Increase) of Non Sedentary Daytime Physical Activity at Week 12 Compared to Baseline No	175 Participants	163 Participants
Number and Percentage of Participants Who Show Increased Levels (>= 10% Increase) of Non Sedentary Daytime Physical Activity at Week 12 Compared to Baseline Yes	28 Participants	31 Participants
Number and Percentage of Participants Who Show Increased Levels (>= 10% Increase) of Non Sedentary Daytime Physical Activity at Week 12 Compared to Baseline Missing	99 Participants	108 Participants

SECONDARY outcome

Timeframe: Week 4, Week 8, Week 12

Population: The Full Analysis Set was considered

The Patient Global Assessment (PGA) is a self-reported tool to assess the patients' subjective rating of their disease activity widely used in HF research. The patients are asked to report functioning or response to an intervention by rating their current condition compared to their pre-intervention condition on a numerical scale: 1) much improved 2) moderately improved 3) a little improved 4) unchanged 5) a little worse 6) moderately worse or 7) much worse.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 8 · Is unchanged	82 Participants	88 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 8 · Is a little worse	14 Participants	11 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 12 · Has (moderately) improved	72 Participants	67 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 12 · Is unchanged	79 Participants	94 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 4 · Has much improved	19 Participants	16 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 4 · Has (moderately) improved	63 Participants	51 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 4 · Has a little improved	94 Participants	64 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 4 · Is unchanged	98 Participants	131 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 4 · Is a little worse	13 Participants	15 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 4 · Is (moderately) worse	3 Participants	5 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 4 · Is much worse	1 Participants	1 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 4 · Missing	11 Participants	19 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 8 · Has much improved	23 Participants	24 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 8 · Has (moderately) improved	79 Participants	73 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 8 · Has a little improved	88 Participants	82 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 8 · Is (moderately) worse	2 Participants	3 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 8 · Is much worse	0 Participants	1 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 8 · Missing	14 Participants	20 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 12 · Has much improved	35 Participants	40 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 12 · Has a little improved	82 Participants	74 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 12 · Is a little worse	12 Participants	7 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 12 · Is (moderately) worse	5 Participants	3 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 12 · Is much worse	2 Participants	2 Participants
Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 Week 12 · Missing	15 Participants	15 Participants

SECONDARY outcome

Timeframe: Week 4, Week 8, Week 12

Population: The Full Analysis Set was considered

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 8 · Improvement	190 Participants	179 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 8 · Is unchanged	82 Participants	88 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 8 · Gets worse	16 Participants	15 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 12 · Is unchanged	79 Participants	94 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 12 · Gets worse	19 Participants	12 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 12 · Missing	15 Participants	15 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 4 · Improvement	176 Participants	131 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 4 · Is unchanged	98 Participants	131 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 4 · Gets worse	17 Participants	21 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 4 · Missing	11 Participants	19 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 8 · Missing	14 Participants	20 Participants
Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) Week 12 · Improvement	189 Participants	181 Participants

SECONDARY outcome

Timeframe: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12

Population: The Full Analysis Set was considered

Non-sedentary physical activity is defined as \>= 178.50 activity counts per minute; Mean daily non-sedentary daytime physical activity were being calculated over weekly and compared to before the inclusion.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 5	507.46 minutes Standard Deviation 129.31	501.70 minutes Standard Deviation 138.78
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 5	1.77 minutes Standard Deviation 71.74	-10.95 minutes Standard Deviation 81.39
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 6	504.15 minutes Standard Deviation 131.05	500.39 minutes Standard Deviation 136.08
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 6	-0.44 minutes Standard Deviation 76.32	-7.91 minutes Standard Deviation 69.71
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 8	497.62 minutes Standard Deviation 130.56	496.45 minutes Standard Deviation 139.12
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 8	-9.49 minutes Standard Deviation 79.10	-9.21 minutes Standard Deviation 75.23
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 9	496.74 minutes Standard Deviation 128.90	497.24 minutes Standard Deviation 131.02
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 11	-12.93 minutes Standard Deviation 74.12	-11.64 minutes Standard Deviation 75.35
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Baseline	512.07 minutes Standard Deviation 126.37	505.31 minutes Standard Deviation 129.74
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 1	527.34 minutes Standard Deviation 129.54	509.28 minutes Standard Deviation 131.75
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 1	22.60 minutes Standard Deviation 62.33	9.88 minutes Standard Deviation 50.17
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 2	531.19 minutes Standard Deviation 133.89	508.70 minutes Standard Deviation 133.69
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 2	22.80 minutes Standard Deviation 70.25	6.19 minutes Standard Deviation 55.14
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 3	525.98 minutes Standard Deviation 126.66	513.63 minutes Standard Deviation 130.58
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 3	13.55 minutes Standard Deviation 66.74	6.40 minutes Standard Deviation 62.63
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 4	519.45 minutes Standard Deviation 133.21	503.25 minutes Standard Deviation 139.48
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 4	11.99 minutes Standard Deviation 60.10	-5.35 minutes Standard Deviation 72.35
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 7	495.06 minutes Standard Deviation 127.80	503.46 minutes Standard Deviation 139.69
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 7	-10.35 minutes Standard Deviation 76.94	-6.54 minutes Standard Deviation 75.77
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 9	-10.09 minutes Standard Deviation 69.93	-10.75 minutes Standard Deviation 75.82
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 10	495.53 minutes Standard Deviation 130.97	500.88 minutes Standard Deviation 138.35
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 10	-9.46 minutes Standard Deviation 80.47	-7.52 minutes Standard Deviation 77.12
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 11	492.28 minutes Standard Deviation 127.19	495.14 minutes Standard Deviation 135.54
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Week 12	492.28 minutes Standard Deviation 127.19	495.14 minutes Standard Deviation 135.54
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals Change from BL at Week 12	-12.93 minutes Standard Deviation 74.12	-11.64 minutes Standard Deviation 75.35

SECONDARY outcome

Timeframe: Baseline, Weeks 0 to 2, Weeks 2 to 4, Weeks 4 to 6, Weeks 6 to 8, Weeks 8 to 10, Weeks 10 to 12

Population: The Full Analysis Set was considered

Non-sedentary physical activity is defined as \>= 178.50 activity counts per minute; Mean daily non-sedentary daytime physical activity were being calculated over two-weekly intervals and compared to before the inclusion.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Change from BL at Week 8	-10.11 minutes Standard Deviation 71.75	-7.62 minutes Standard Deviation 69.96
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Weeks 8 to 10	496.57 minutes Standard Deviation 126.68	497.02 minutes Standard Deviation 132.96
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Change from BL at Week 10	-8.44 minutes Standard Deviation 68.35	-8.75 minutes Standard Deviation 71.50
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Weeks 10 to 12	483.20 minutes Standard Deviation 121.43	493.41 minutes Standard Deviation 130.00
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Baseline	512.07 minutes Standard Deviation 126.37	505.31 minutes Standard Deviation 129.74
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Weeks 0 to 2	529.63 minutes Standard Deviation 129.31	509.02 minutes Standard Deviation 129.97
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Change from BL at Week 2	22.88 minutes Standard Deviation 60.90	8.06 minutes Standard Deviation 45.65
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Weeks 2 to 4	522.30 minutes Standard Deviation 126.68	508.57 minutes Standard Deviation 131.41
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Change from BL at Week 4	12.04 minutes Standard Deviation 54.84	0.55 minutes Standard Deviation 60.23
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Weeks 4 to 6	505.54 minutes Standard Deviation 127.40	500.49 minutes Standard Deviation 135.70
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Change from BL at Week 6	0.21 minutes Standard Deviation 68.47	-10.86 minutes Standard Deviation 72.76
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Weeks 6 to 8	495.94 minutes Standard Deviation 124.78	500.92 minutes Standard Deviation 135.26
Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals Change from BL at Week 12	-21.17 minutes Standard Deviation 68.77	-13.93 minutes Standard Deviation 72.85

SECONDARY outcome

Timeframe: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12

Population: The Full Analysis Set was considered

The average number of minutes per day spent in light non-sedentary physical activity was being calculated over 7 day epochs. Non-sedentary physical activity is defined as \>= 178.5 activity counts per minute and light physical activity is defined as 178.5 - 565.5 counts per minute.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Baseline	251.94 minutes Standard Deviation 50.54	247.30 minutes Standard Deviation 58.70
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 1	263.17 minutes Standard Deviation 55.85	251.37 minutes Standard Deviation 58.13
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 1	14.10 minutes Standard Deviation 31.15	6.28 minutes Standard Deviation 27.98
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 2	262.42 minutes Standard Deviation 55.12	248.33 minutes Standard Deviation 57.81
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 2	10.91 minutes Standard Deviation 36.10	1.58 minutes Standard Deviation 28.80
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 3	9.68 minutes Standard Deviation 33.10	3.61 minutes Standard Deviation 31.85
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 4	256.10 minutes Standard Deviation 52.61	246.97 minutes Standard Deviation 58.06
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 5	2.71 minutes Standard Deviation 37.90	-5.77 minutes Standard Deviation 37.14
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 6	252.10 minutes Standard Deviation 56.73	244.25 minutes Standard Deviation 57.33
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 6	1.08 minutes Standard Deviation 38.80	-4.72 minutes Standard Deviation 36.44
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 7	251.02 minutes Standard Deviation 52.09	244.85 minutes Standard Deviation 57.32
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 7	-0.88 minutes Standard Deviation 38.88	-3.18 minutes Standard Deviation 37.27
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 8	251.46 minutes Standard Deviation 52.21	245.02 minutes Standard Deviation 59.31
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 8	-1.71 minutes Standard Deviation 38.69	-2.41 minutes Standard Deviation 36.53
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 9	250.04 minutes Standard Deviation 52.64	254.84 minutes Standard Deviation 56.31
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 9	-2.54 minutes Standard Deviation 35.74	-4.52 minutes Standard Deviation 37.14
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 10	248.33 minutes Standard Deviation 54.44	245.62 minutes Standard Deviation 58.69
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 10	-3.43 minutes Standard Deviation 42.11	-2.65 minutes Standard Deviation 36.76
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 11	248.19 minutes Standard Deviation 53.09	244.83 minutes Standard Deviation 59.77
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 11	-3.86 minutes Standard Deviation 39.67	-3.13 minutes Standard Deviation 34.23
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 12	239.30 minutes Standard Deviation 52.76	243.63 minutes Standard Deviation 56.92
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 12	-11.98 minutes Standard Deviation 42.07	-6.55 minutes Standard Deviation 35.79
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 3	261.80 minutes Standard Deviation 52.68	251.12 minutes Standard Deviation 57.48
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Change from BL at Week 4	5.14 minutes Standard Deviation 31.12	-1.77 minutes Standard Deviation 33.49
Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity Week 5	253.98 minutes Standard Deviation 54.75	243.71 minutes Standard Deviation 59.17

SECONDARY outcome

Timeframe: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12

Population: The Full Analysis Set was considered

The average number of minutes per day spent in moderate to vigorous non-sedentary physical activity was being calculated over 7 day epochs. Non-sedentary physical activity is defined as \>= 178.5 activity counts per minute and moderate-to-vigorous activity is defined as \> 565.5 counts per minute.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 1	8.50 minutes Standard Deviation 45.86	3.60 minutes Standard Deviation 39.79
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 2	268.77 minutes Standard Deviation 114.83	260.37 minutes Standard Deviation 116.00
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 2	11.89 minutes Standard Deviation 50.98	4.61 minutes Standard Deviation 45.53
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 3	3.87 minutes Standard Deviation 49.53	2.80 minutes Standard Deviation 51.23
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 4	263.35 minutes Standard Deviation 114.86	256.28 minutes Standard Deviation 115.82
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 4	6.85 minutes Standard Deviation 43.45	-3.58 minutes Standard Deviation 56.76
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 5	253.48 minutes Standard Deviation 108.52	257.99 minutes Standard Deviation 115.65
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 5	-0.93 minutes Standard Deviation 51.57	-5.18 minutes Standard Deviation 66.01
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 8	-7.78 minutes Standard Deviation 57.13	-6.80 minutes Standard Deviation 57.90
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 10	247.20 minutes Standard Deviation 107.41	255.26 minutes Standard Deviation 116.88
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 12	-20.52 minutes Standard Deviation 58.37	-11.57 minutes Standard Deviation 64.90
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Baseline	260.13 minutes Standard Deviation 110.94	258.01 minutes Standard Deviation 111.73
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 1	264.16 minutes Standard Deviation 109.31	257.92 minutes Standard Deviation 111.47
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 3	264.19 minutes Standard Deviation 108.10	262.51 minutes Standard Deviation 111.15
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 6	252.05 minutes Standard Deviation 108.75	256.14 minutes Standard Deviation 115.35
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 6	-1.52 minutes Standard Deviation 55.23	-3.19 minutes Standard Deviation 54.72
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 7	244.04 minutes Standard Deviation 105.32	258.61 minutes Standard Deviation 118.51
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 7	-9.47 minutes Standard Deviation 57.67	-3.35 minutes Standard Deviation 56.28
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 8	246.16 minutes Standard Deviation 109.03	251.42 minutes Standard Deviation 113.84
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 9	246.70 minutes Standard Deviation 106.78	251.40 minutes Standard Deviation 108.51
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 9	-7.55 minutes Standard Deviation 54.98	-6.23 minutes Standard Deviation 57.68
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 10	-6.03 minutes Standard Deviation 57.08	-4.86 minutes Standard Deviation 59.50
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 11	244.09 minutes Standard Deviation 104.33	250.31 minutes Standard Deviation 113.81
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 11	-9.07 minutes Standard Deviation 51.95	-8.51 minutes Standard Deviation 61.45
Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 12	237.15 minutes Standard Deviation 100.32	248.08 minutes Standard Deviation 113.51

SECONDARY outcome

Timeframe: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12

Population: The Full Analysis Set was considered

Non-sedentary physical activity is defined as \>= 178.5 activity counts per minute; The total time spent in non-sedentary physical activity was being calculated for each patient in weekly intervals and the temporal course for each patient was assessed.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Baseline	3616.87 minutes Standard Deviation 964.92	3528.56 minutes Standard Deviation 993.10
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 1	3676.46 minutes Standard Deviation 923.85	3560.10 minutes Standard Deviation 916.16
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 1	103.29 minutes Standard Deviation 509.20	82.48 minutes Standard Deviation 588.19
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 2	3691.24 minutes Standard Deviation 953.03	3557.71 minutes Standard Deviation 940.60
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 2	76.23 minutes Standard Deviation 563.79	52.38 minutes Standard Deviation 600.08
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 5	-116.74 minutes Standard Deviation 607.31	-79.18 minutes Standard Deviation 817.71
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 8	3466.82 minutes Standard Deviation 936.51	3457.74 minutes Standard Deviation 993.56
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 9	3470.69 minutes Standard Deviation 913.06	3447.28 minutes Standard Deviation 932.67
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 10	-119.41 minutes Standard Deviation 648.17	-68.93 minutes Standard Deviation 711.22
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 11	3406.56 minutes Standard Deviation 910.84	3436.96 minutes Standard Deviation 971.78
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 11	-170.14 minutes Standard Deviation 632.53	-120.35 minutes Standard Deviation 707.11
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 3	3668.25 minutes Standard Deviation 894.91	3580.54 minutes Standard Deviation 922.70
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 3	25.28 minutes Standard Deviation 571.36	34.56 minutes Standard Deviation 663.68
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 4	3608.39 minutes Standard Deviation 936.87	3482.15 minutes Standard Deviation 991.15
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 4	5.10 minutes Standard Deviation 497.55	-56.23 minutes Standard Deviation 748.35
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 5	3488.43 minutes Standard Deviation 944.87	3458.65 minutes Standard Deviation 973.75
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 6	3519.12 minutes Standard Deviation 922.58	3489.15 minutes Standard Deviation 962.55
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 6	-72.08 minutes Standard Deviation 569.61	-21.73 minutes Standard Deviation 724.96
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 7	3444.52 minutes Standard Deviation 892.15	3502.67 minutes Standard Deviation 977.43
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 7	-143.38 minutes Standard Deviation 605.25	-36.18 minutes Standard Deviation 709.43
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 8	-130.59 minutes Standard Deviation 631.30	-59.92 minutes Standard Deviation 716.74
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 9	-131.28 minutes Standard Deviation 549.54	-108.48 minutes Standard Deviation 719.58
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 10	3444.77 minutes Standard Deviation 947.18	3489.68 minutes Standard Deviation 964.08
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Week 12	3093.96 minutes Standard Deviation 913.14	3234.90 minutes Standard Deviation 991.50
Total Weekly Time Spent in Non-sedentary Daytime Physical Activity Change from BL at Week 12	-506.82 minutes Standard Deviation 792.71	-339.15 minutes Standard Deviation 786.06

SECONDARY outcome

Timeframe: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12

Population: The Full Analysis Set was considered

Light non-sedentary daytime physical activity is defined as between 178.5 - 565.5 counts per minute; The time spent in light non-sedentary physical activity was being calculated for each patient in weekly intervals and the temporal course for each patient was assessed.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 1	81.84 minutes Standard Deviation 255.91	53.74 minutes Standard Deviation 282.22
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 3	46.05 minutes Standard Deviation 281.11	24.88 minutes Standard Deviation 313.52
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 7	1747.03 minutes Standard Deviation 366.43	1702.58 minutes Standard Deviation 399.11
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 7	-32.03 minutes Standard Deviation 307.16	-17.71 minutes Standard Deviation 322.33
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 8	1750.02 minutes Standard Deviation 377.35	1705.09 minutes Standard Deviation 424.99
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 8	-37.50 minutes Standard Deviation 323.19	-17.49 minutes Standard Deviation 318.83
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 9	-36.47 minutes Standard Deviation 289.67	-43.21 minutes Standard Deviation 341.30
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 10	-46.95 minutes Standard Deviation 339.81	-22.01 minutes Standard Deviation 314.65
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 11	-60.08 minutes Standard Deviation 319.85	-40.52 minutes Standard Deviation 313.76
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 12	1559.62 minutes Standard Deviation 428.02	1607.33 minutes Standard Deviation 449.83
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Baseline	1773.14 minutes Standard Deviation 392.22	1721.50 minutes Standard Deviation 452.26
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 1	1834.71 minutes Standard Deviation 400.46	1757.76 minutes Standard Deviation 407.14
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 2	1823.86 minutes Standard Deviation 396.55	1736.64 minutes Standard Deviation 407.45
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 2	46.26 minutes Standard Deviation 301.74	17.26 minutes Standard Deviation 280.12
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 3	1826.38 minutes Standard Deviation 376.72	1751.95 minutes Standard Deviation 410.11
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 4	1778.88 minutes Standard Deviation 372.86	1707.68 minutes Standard Deviation 410.73
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 4	9.17 minutes Standard Deviation 275.92	-18.74 minutes Standard Deviation 346.02
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 5	1745.87 minutes Standard Deviation 406.21	1683.08 minutes Standard Deviation 429.50
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 5	-36.66 minutes Standard Deviation 307.01	-37.98 minutes Standard Deviation 369.53
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 6	1759.09 minutes Standard Deviation 397.67	1701.89 minutes Standard Deviation 405.01
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 6	-17.85 minutes Standard Deviation 290.75	-16.56 minutes Standard Deviation 343.51
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 9	1746.73 minutes Standard Deviation 375.07	1706.26 minutes Standard Deviation 407.89
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 10	1724.72 minutes Standard Deviation 395.95	1712.55 minutes Standard Deviation 412.82
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Week 11	1717.08 minutes Standard Deviation 386.33	1697.81 minutes Standard Deviation 429.44
Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity Change from BL at Week 12	-210.49 minutes Standard Deviation 390.17	-144.96 minutes Standard Deviation 339.29

SECONDARY outcome

Timeframe: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12

Population: The Full Analysis Set was considered

Moderate-to-vigorous non-sedentary physical activity is defined as \> 565.5 counts per minute. The total time spent in moderate-to-vigorous non-sedentary physical activity was being calculated for each patient in weekly intervals and the temporal course for each patient was assessed.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Baseline	1843.73 minutes Standard Deviation 830.30	1807.07 minutes Standard Deviation 815.89
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 1	1841.76 minutes Standard Deviation 769.54	1802.34 minutes Standard Deviation 775.36
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 1	21.45 minutes Standard Deviation 373.16	28.75 minutes Standard Deviation 404.20
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 3	1841.87 minutes Standard Deviation 755.88	1828.59 minutes Standard Deviation 777.65
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 3	-20.77 minutes Standard Deviation 425.19	9.68 minutes Standard Deviation 458.99
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 4	1829.51 minutes Standard Deviation 801.93	1774.46 minutes Standard Deviation 815.93
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 4	-4.07 minutes Standard Deviation 344.29	-37.49 minutes Standard Deviation 506.27
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 5	1742.56 minutes Standard Deviation 767.53	1775.57 minutes Standard Deviation 798.92
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 6	1760.03 minutes Standard Deviation 763.64	1787.26 minutes Standard Deviation 810.30
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 6	-54.23 minutes Standard Deviation 416.05	-5.17 minutes Standard Deviation 509.74
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 7	1697.49 minutes Standard Deviation 732.18	1800.09 minutes Standard Deviation 829.37
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 7	-111.35 minutes Standard Deviation 438.85	-18.47 minutes Standard Deviation 505.11
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 8	1716.80 minutes Standard Deviation 769.31	1752.65 minutes Standard Deviation 802.46
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 8	-93.09 minutes Standard Deviation 429.65	-42.43 minutes Standard Deviation 522.80
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 10	-72.46 minutes Standard Deviation 442.80	-46.92 minutes Standard Deviation 514.49
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 11	1689.48 minutes Standard Deviation 731.77	1739.15 minutes Standard Deviation 803.36
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 12	-296.33 minutes Standard Deviation 525.81	-194.19 minutes Standard Deviation 564.53
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 2	1867.37 minutes Standard Deviation 806.56	1821.07 minutes Standard Deviation 813.27
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 2	29.97 minutes Standard Deviation 383.31	35.13 minutes Standard Deviation 432.43
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 5	-80.08 minutes Standard Deviation 423.07	-41.20 minutes Standard Deviation 577.49
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 9	1723.96 minutes Standard Deviation 750.60	1741.02 minutes Standard Deviation 757.26
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 9	-94.81 minutes Standard Deviation 407.63	-65.27 minutes Standard Deviation 492.38
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 10	1720.06 minutes Standard Deviation 760.72	1777.14 minutes Standard Deviation 811.27
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Change from BL at Week 11	-110.06 minutes Standard Deviation 432.47	-79.83 minutes Standard Deviation 516.05
Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity Week 12	1534.35 minutes Standard Deviation 678.12	1627.57 minutes Standard Deviation 778.70

SECONDARY outcome

Timeframe: Baseline, Week 2, Week 4, Week 6, Week 8 and Week 12

Population: The Full Analysis Set was considered

The peak 6 min walk (M6min) is a parameter derived by validated algorithms of the software that are used to preprocess actigraphy data. The parameter reflected the peak 6 minutes of day time physical activity. The mean daily 6-minute walking test was being calculated over 14 day intervals.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=302 Participants LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=302 Participants Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Baseline	189.08 minutes Standard Deviation 67.75	182.52 minutes Standard Deviation 60.09
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Week 2	193.54 minutes Standard Deviation 77.30	184.46 minutes Standard Deviation 59.49
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Change from BL at Week 2	6.18 minutes Standard Deviation 46.72	3.52 minutes Standard Deviation 32.16
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Week 4	191.86 minutes Standard Deviation 80.21	181.11 minutes Standard Deviation 61.75
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Change from BL at Week 4	5.47 minutes Standard Deviation 50.93	-0.23 minutes Standard Deviation 40.44
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Week 6	191.21 minutes Standard Deviation 77.38	181.11 minutes Standard Deviation 55.07
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Change from BL at Week 6	2.69 minutes Standard Deviation 42.51	-1.02 minutes Standard Deviation 38.82
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Week 8	183.96 minutes Standard Deviation 70.54	180.92 minutes Standard Deviation 57.28
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Change from BL at Week 8	-2.71 minutes Standard Deviation 41.43	-0.22 minutes Standard Deviation 38.05
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Week 12	184.42 minutes Standard Deviation 67.09	180.44 minutes Standard Deviation 55.36
Change From Baseline in Peak Six Minutes of Daytime Physical Activity Change from BL at Week 12	-1.07 minutes Standard Deviation 49.32	-2.45 minutes Standard Deviation 39.15

Adverse Events

LCZ696 (Sacubitril/Valsartan)

Serious events: 19 serious events

Other events: 168 other events

Deaths: 1 deaths

Enalapril

Serious events: 28 serious events

Other events: 143 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	LCZ696 (Sacubitril/Valsartan) n=309 participants at risk LCZ696 (Sacubitril/Valsartan) or its matching placebo twice a day for 12 weeks. Patients began study treatment (Sacubitril/Valsartan) at a specific dose level according to their pre-study ACEI/ARB dose (1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ)) or matching placebo and were up-titrated according to an up-titration scheme.	Enalapril n=310 participants at risk Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.
Blood and lymphatic system disorders Anaemia	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Acute coronary syndrome	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Acute myocardial infarction	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Angina pectoris	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Atrial fibrillation	1.3% 4/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.65% 2/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Atrial flutter	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Cardiac arrest	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.65% 2/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Cardiac failure	1.3% 4/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	2.3% 7/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Cardiac failure congestive	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Coronary artery disease	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Myocardial infarction	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Tachycardia	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Ventricular arrhythmia	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Cardiac disorders Ventricular fibrillation	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Gastrointestinal disorders Abdominal pain	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Gastrointestinal disorders Gastric haemorrhage	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Gastrointestinal disorders Inguinal hernia	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Gastrointestinal disorders Intestinal perforation	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
General disorders Death	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
General disorders Pyrexia	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.65% 2/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Infections and infestations Diverticulitis	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Infections and infestations Epididymitis	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Infections and infestations Pneumonia	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.65% 2/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Infections and infestations Respiratory tract infection	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Infections and infestations Sepsis	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Infections and infestations Upper respiratory tract infection	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Infections and infestations Urinary tract infection	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Injury, poisoning and procedural complications Coronary bypass thrombosis	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic bronchial carcinoma	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Nervous system disorders Paraesthesia	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Nervous system disorders Stroke in evolution	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Nervous system disorders Syncope	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Renal and urinary disorders Haematuria	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Renal and urinary disorders Renal failure	0.65% 2/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Renal and urinary disorders Urinary retention	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Renal and urinary disorders Urogenital haemorrhage	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Reproductive system and breast disorders Prostatitis	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Skin and subcutaneous tissue disorders Skin necrosis	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Surgical and medical procedures Renal lithiasis prophylaxis	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Vascular disorders Intermittent claudication	0.32% 1/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.00% 0/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Vascular disorders Thrombosis	0.00% 0/309 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.	0.32% 1/310 • Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.