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Clinical Trial Results:
A multi-center, prospective, randomized, double-blind study to assess the impact of sacubitril/valsartan vs. enalapril on daily physical activity using a wrist worn actigraphy device in adult chronic heart failure patients

Summary
EudraCT number	2016-003085-32
Trial protocol	DE LT SE EE DK LV BE ES FI FR BG NL IS GR CZ GB
Global end of trial date	11 Apr 2018

Results information
Results version number	v1
This version publication date	27 Apr 2019
First version publication date	27 Apr 2019
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CLCZ696B3301

ISRCTN number

US NCT number

NCT02900378

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

11 Apr 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 Apr 2018

Global end of trial reached?

Yes

Global end of trial date

11 Apr 2018

Was the trial ended prematurely?

Main objective of the trial

The primary objectives were: • To assess changes from baseline (week 0) in exercise capacity assessed by means of the 6-minute walking test (6MWT) at week 12 in sacubitril/valsartan vs. enalapril treated patients. • To assess changes in daily non-sedentary daytime activity between baseline and after 12 weeks of treatment in sacubitril/valsartan vs. enalapril treated patients.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Dec 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 22

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

Czech Republic: 47

Country: Number of subjects enrolled

Denmark: 25

Country: Number of subjects enrolled

Estonia: 56

Country: Number of subjects enrolled

Finland: 6

Country: Number of subjects enrolled

France: 11

Country: Number of subjects enrolled

Germany: 134

Country: Number of subjects enrolled

Greece: 30

Country: Number of subjects enrolled

Iceland: 11

Country: Number of subjects enrolled

Ireland: 1

Country: Number of subjects enrolled

Latvia: 22

Country: Number of subjects enrolled

Lithuania: 30

Country: Number of subjects enrolled

Netherlands: 29

Country: Number of subjects enrolled

Norway: 5

Country: Number of subjects enrolled

Poland: 34

Country: Number of subjects enrolled

Spain: 110

Country: Number of subjects enrolled

Sweden: 8

Country: Number of subjects enrolled

United Kingdom: 26

Worldwide total number of subjects

621

EEA total number of subjects

621

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

248

From 65 to 84 years

356

85 years and over

Subject disposition

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Recruitment details

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).

Screening details

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).

Period 1 title

Randomization (Visit 2)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Are arms mutually exclusive

Yes

LCZ696 (Sacubitril/Valsartan)

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

LCZ696

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Twice daliy: Sacubitril/valsartan 24 mg/26 mg (LCZ696 50 mg), Sacubitril/valsartan 49 mg/51 mg (LCZ696 100 mg) or Sacubitril/valsartan 97 mg/103 mg (LCZ696 200 mg)

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Twice daliy: Placebo to match sacubitril/valsartan 24 mg/26 mg (LCZ696 50 mg), Placebo to match sacubitril/valsartan 49 mg/51 mg (LCZ696 100 mg) or Placebo to match sacubitril/valsartan 97 mg/103 mg (LCZ696 200 mg)

Enalapril

Arm description

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.

Arm type

Active comparator

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Twice daily: Placebo to match enalapril 2.5 mg, Placebo to match enalapril 5 mg or Placebo to match enalapril 10 mg

Investigational medicinal product name

Enalapril

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Twice daily: Enalapril 2.5 mg, Enalapril 5 mg or Placebo to match enalapril 10 mg

Number of subjects in period 1	LCZ696 (Sacubitril/Valsartan)	Enalapril
Started	310	311
Completed	287	283
Not completed	23	28
Adverse event, serious fatal	1	4
Non-compliance with Study Drug	1	1
Adverse event, non-fatal	14	11
Protocol Deviation	1	7
Withdrawal by Parent/Guardian	5	3
Lost to follow-up	1	-
Withdrawal of Informed Consent	-	2

Period 2 title

Treatment Phase

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Are arms mutually exclusive

LCZ696 (Sacubitril/Valsartan)

Arm description

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

LCZ696

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Twice daliy: Sacubitril/valsartan 24 mg/26 mg (LCZ696 50 mg), Sacubitril/valsartan 49 mg/51 mg (LCZ696 100 mg) or Sacubitril/valsartan 97 mg/103 mg (LCZ696 200 mg)

Enalapril

Arm description

Arm type

Active comparator

Investigational medicinal product name

Enalapril

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Twice daily: Enalapril 2.5 mg, Enalapril 5 mg or Placebo to match enalapril 10 mg

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Twice daily: Placebo to match enalapril 2.5 mg, Placebo to match enalapril 5 mg or Placebo to match enalapril 10 mg

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: All randomized patients (irrespective as to whether or not they were treated) are included in the randomized set and represented in Period 1. All Demographic and other baseline characteristics were done on the safety and full analysis sets which are represented in Period 2.

Number of subjects in period 2	LCZ696 (Sacubitril/Valsartan)	Enalapril
Started	309	310
Full Analysis Set	302 ^[2]	302 ^[3]
Completed	309	310

Notes
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The full analysis set (FAS) comprised all patients of the safety data set who provided the baseline value and any post-baseline value of at least one primary endpoint (6MWT or daily non-sedentary daytime activity); 302 patients in each treatment group. The number of patients that started/completed correspond to the safety data set (SAF) consisting of all patients who receivedat least one dose of study medication.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The full analysis set (FAS) comprised all patients of the safety data set who provided the baseline value and any post-baseline value of at least one primary endpoint (6MWT or daily non-sedentary daytime activity); 302 patients in each treatment group. The number of patients that started/completed correspond to the safety data set (SAF) consisting of all patients who receivedat least one dose of study medication.

Baseline characteristics

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Reporting group title

LCZ696 (Sacubitril/Valsartan)

Reporting group description

Reporting group title

Enalapril

Reporting group description

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: The worldwide number of enrolled patients in the trial (621) is the total number of randomized patients (irrespective as to whether or not they were treated). All Demographic and other baseline characteristics were done on the safety and full analysis sets.

Reporting group values	LCZ696 (Sacubitril/Valsartan)	Enalapril	Total
Number of subjects	309	310	619
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	118	130	248
From 65-84 years	180	174	354
85 years and over	11	6	17
Age Continuous
Units: Years
arithmetic mean (standard deviation)	67.16 ± 11.04	66.62 ± 10.45	-
Sex: Female, Male
Units: Subjects
Female	71	61	132
Male	238	249	487
Race/Ethnicity, Customized
Units: Subjects
Black or African American	1	0	1
White	298	299	597
Missing	10	11	21

Subject analysis set title

Safety data set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

The safety data set (SAF) consisted of all patients who received at least one dose of study medication. Safety analyses were performed based on the SAF, and according to the treatment received.

Subject analysis set title

Full analysis set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

The full analysis set (FAS) comprised all patients of the safety data set who provided the baseline value and any post-baseline value of at least one primary endpoint (6MWT or daily non-sedentary daytime activity).

Subject analysis sets values	Safety data set (SAF)	Full analysis set (FAS)
Number of subjects	619	604
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	248	242
From 65-84 years	354	347
85 years and over	17	15
Age Continuous
Units: Years
arithmetic mean (standard deviation)	66.89 ± 10.74	66.81 ± 10.72
Sex: Female, Male
Units: Subjects
Female	132	128
Male	487	476
Race/Ethnicity, Customized
Units: Subjects
Black or African American	1	1
White	597	582
Missing	21	21

End points

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Reporting group title

LCZ696 (Sacubitril/Valsartan)

Reporting group description

Reporting group title

Enalapril

Reporting group description

Reporting group title

LCZ696 (Sacubitril/Valsartan)

Reporting group description

Reporting group title

Enalapril

Reporting group description

Subject analysis set title

Safety data set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

The safety data set (SAF) consisted of all patients who received at least one dose of study medication. Safety analyses were performed based on the SAF, and according to the treatment received.

Subject analysis set title

Full analysis set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Change from Baseline (Week 0) in the Six Minute Walk Test (6MWT) at end of Study (Week 12)

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End point title

Change from Baseline (Week 0) in the Six Minute Walk Test (6MWT) at end of Study (Week 12)

End point description

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.

End point type

Primary

End point timeframe

Baseline, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	310
Units: meters
arithmetic mean (standard deviation)
Baseline (FAS)	365.37 ± 108.18	371.08 ± 104.41
Week 12 (FAS)	395.80 ± 113.11	395.33 ± 105.94
Change from BL at Week 12 (FAS)	31.57 ± 67.35	24.89 ± 51.64
Baseline (FAS without AE/SAE)	364.72 ± 106.86	371.18 ± 105.13
Week 12 (FAS without AE/SAE)	399.31 ± 110.54	396.02 ± 106.39
Change from BL at Week 12 (FAS without AE/SAE)	35.75 ± 58.76	25.87 ± 51.73

Change from BL at Week 12 (FAS)

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

612

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2464 ^[1]

Method

ANCOVA

Parameter type

Differences of least square means

Point estimate

5.68

Confidence interval

level

95%

sides

2-sided

lower limit

-3.93

upper limit

15.29

Variability estimate

Standard error of the mean

Dispersion value

4.89

Notes
[1] - The comparison of treatment groups were out using an analysis of covariance (ANCOVA) model adjusting for treatment and baseline NYHA class (NYHA II vs. III/IV) and the 6MWT baseline value as covariates.

Change from BL at Week 12 (FAS without AE/SAE)

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

612

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0503 ^[2]

Method

ANCOVA

Parameter type

Differences of least square means

Point estimate

8.98

Confidence interval

level

97.5%

sides

2-sided

lower limit

-1.31

upper limit

19.27

Variability estimate

Standard error of the mean

Dispersion value

4.58

Notes
[2] - The comparison of treatment groups were out using an analysis of covariance (ANCOVA) model adjusting for treatment and baseline NYHA class (NYHA II vs. III/IV) and the 6MWT baseline value as covariates.

Primary: Change from Baseline (Week 0) in mean daily non-sedentary daytime activity at end of Study (Week 12)

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End point title

Change from Baseline (Week 0) in mean daily non-sedentary daytime activity at end of Study (Week 12)

End point description

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).

End point type

Primary

End point timeframe

Baseline, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: minutes
arithmetic mean (standard deviation)
Baseline (FAS with MI)	510.11 ± 128.08	506.81 ± 139.60
Week 12 (FAS with MI)	479.69 ± 124.23	487.53 ± 126.84
Change from BL at Week 12 (FAS with MI)	-30.42 ± 102.55	-19.28 ± 104.04
Baseline (FAS with LOCF)	512.07 ± 126.37	505.31 ± 129.74
Week 12 (FAS with LOCF)	489.43 ± 127.36	490.09 ± 127.82
Change from BL at Week 12 (FAS with LOCF)	-21.88 ± 68.55	-15.41 ± 74.45
Baseline (FAS without MI/LOCF)	512.07 ± 126.37	505.31 ± 129.74
Week 12 (FAS without MI/LOCF)	479.81 ± 122.45	486.85 ± 128.70
Change from BL at Week 12 (FAS without MI/LOCF)	-25.14 ± 69.11	-20.51 ± 72.52

Change from BL at Week 12 (FAS with MI)

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4769 ^[3]

Method

ANCOVA

Parameter type

Differences of least square means

Point estimate

-6.14

Confidence interval

level

97.5%

sides

2-sided

lower limit

-25.7

upper limit

13.41

Variability estimate

Standard error of the mean

Dispersion value

8.61

Notes
[3] - The comparison of treatment groups were carried out using an ANCOVA model adjusting for treatment, baseline NYHA class (NYHA II vs. III/IV) and the daily non-sedentary daytime activity baseline value as covariates.

Change from BL at Week 12 (FAS without MI/LOCF)

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3513 ^[4]

Method

ANCOVA

Parameter type

Differences of least square means

Point estimate

-6.24

Confidence interval

level

95%

sides

2-sided

lower limit

-19.39

upper limit

6.91

Variability estimate

Standard error of the mean

Dispersion value

6.69

Notes
[4] - The comparison of treatment groups were carried out using an ANCOVA model adjusting for treatment, baseline NYHA class (NYHA II vs. III/IV) and the daily non-sedentary daytime activity baseline value as covariates.

Change from BL at Week 12 (FAS with LOCF)

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3463 ^[5]

Method

ANCOVA

Parameter type

Differences of least square means

Point estimate

-5.67

Confidence interval

level

95%

sides

2-sided

lower limit

-17.48

upper limit

6.14

Variability estimate

Standard error of the mean

Dispersion value

6.01

Notes
[5] - The comparison of treatment groups were carried out using an ANCOVA model adjusting for treatment, baseline NYHA class (NYHA II vs. III/IV) and the daily non-sedentary daytime activity baseline value as covariates.

Secondary: Proportion of patients with improved performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS

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End point title

Proportion of patients with improved performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS

End point description

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

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: Participants
number (not applicable)
No	142	153
Yes	149	129
Missing	11	20

FAS population

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Odds ratio (OR)

Point estimate

1.228

Confidence interval

level

95%

sides

2-sided

lower limit

0.882

upper limit

1.708

Secondary: Proportion of patients with improved performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS subset without AE/SAE

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End point title

Proportion of patients with improved performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS subset without AE/SAE

End point description

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

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	290	294
Units: Participants
number (not applicable)
No	133	146
Yes	149	129
Missing	8	19

FAS subset without AE/SAE

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

584

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Odds ratio (OR)

Point estimate

1.251

Confidence interval

level

95%

sides

2-sided

lower limit

0.895

upper limit

1.748

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked equal to or less than 300 meters at Baseline - FAS

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End point title

Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked equal to or less than 300 meters at Baseline - FAS

End point description

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.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	78	65
Units: Participants
number (not applicable)
No	35	31
Yes	41	29
Missing	2	5

FAS population

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Odds ratio (OR)

Point estimate

1.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.634

upper limit

2.464

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked equal to or less than 300 meters at Baseline - FAS subset without AE/SAE

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End point title

Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked equal to or less than 300 meters at Baseline - FAS subset without AE/SAE

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	75	63
Units: Participants
number (not applicable)
No	33	30
Yes	41	29
Missing	1	4

FAS subset without AE/SAE

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Odds ratio (OR)

Point estimate

1.28

Confidence interval

level

95%

sides

2-sided

lower limit

0.644

upper limit

2.544

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked 100-450 meters at Baseline - FAS

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End point title

Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked 100-450 meters at Baseline - FAS

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	238	238
Units: Participants
number (not applicable)
No	109	121
Yes	122	105
Missing	7	12

FAS population

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

476

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Odds ratio (OR)

Point estimate

1.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.863

upper limit

1.811

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked 100-450 meters at Baseline - FAS subset without AE/SAE

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End point title

Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked 100-450 meters at Baseline - FAS subset without AE/SAE

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	230	230
Units: Participants
number (not applicable)
No	103	115
Yes	122	105
Missing	5	11

FAS subset without AE/SAE

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Odds ratio (OR)

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.865

upper limit

1.834

Secondary: Change from Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8

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End point title

Change from Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8

End point description

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 walf 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.

End point type

Secondary

End point timeframe

Baseline, Week 4 and Week 8

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: meters
arithmetic mean (standard deviation)
Baseline (FAS)	365.37 ± 108.18	371.08 ± 104.41
Week 4 (FAS)	385.22 ± 110.55	385.02 ± 109.92
Change from BL at Week 4 (FAS)	19.13 ± 49.16	13.72 ± 51.39
Week 8 (FAS)	395.28 ± 112.05	391.72 ± 108.99
Change from BL at Week 8 (FAS)	28.72 ± 57.99	21.15 ± 52.75
Baseline (FAS without AE/SAE)	364.72 ± 106.86	371.18 ± 105.13
Week 4 (FAS without AE/SAE)	384.58 ± 107.69	385.92 ± 110.81
Change from BL at Week 4 (FAS without AE/SAE)	18.91 ± 49.63	14.45 ± 51.48
Week 8 (FAS without AE/SAE)	396.64 ± 110.65	391.82 ± 109.72
Change from BL at Week 8 (FAS without AE/SAE)	30.38 ± 57.07	21.51 ± 52.99

Change from BL at Week 4 (FAS)

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1814

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 4 (FAS without AE/SAE)

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3315

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 8 (FAS)

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2414

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 8 (FAS without AE/SAE)

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1793

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Proportion of patients who show increased levels (>= 10% increase) of non sedentary daytime physical activity at Week 12 compared to Baseline

Top of page

End point title

Proportion of patients who show increased levels (>= 10% increase) of non sedentary daytime physical activity at Week 12 compared to Baseline

End point description

Non sedentary physical activity is defined as >= 178.50 activity counts per minute; the everage 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)

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: Participants
number (not applicable)
No	175	163
Yes	28	31
Missing	99	108

>=10% increase level at week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Odds ratio (OR)

Point estimate

0.821

Confidence interval

level

95%

sides

2-sided

lower limit

0.462

upper limit

1.457

Secondary: Proportion of patients achieving PGA Score at Weeks 4, 8 and 12

Top of page

End point title

Proportion of patients achieving PGA Score at Weeks 4, 8 and 12

End point description

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.

End point type

Secondary

End point timeframe

Week 4, Week 8, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: Participants
number (not applicable)
Week 4\|Has much improved	19	16
Week 8\|Has much improved	23	24
Week 12\|Has much improved	35	40
Week 4\|Has (moderately) improved	63	51
Week 8\|Has (moderately) improved	79	73
Week 12\|Has (moderately) improved	72	67
Week 4\|Has a little improved	94	64
Week 8\|Has a little improved	88	82
Week 12\|Has a little improved	82	74
Week 4\|Is unchanged	98	131
Week 8\|Is unchanged	82	88
Week 12\|Is unchanged	79	94
Week 4\|Is a little worse	13	15
Week 8\|Is a little worse	14	11
Week 12\|Is a little worse	12	7
Week 4\|Is (moderately) worse	3	5
Week 8\|Is (moderately) worse	14	11
Week 12\|Is (moderately) worse	5	3
Week 4\|Is much worse	1	1
Week 8\|Is much worse	0	1
Week 12\|Is much worse	2	2
Week 4\|Missing	11	19
Week 8\|Missing	14	20
Week 12\|Missing	15	15

Week 4

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0515

Method

Chi-squared

Confidence interval

Week 8

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9025

Method

Chi-squared

Confidence interval

Week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6713

Method

Chi-squared

Confidence interval

Secondary: Proportion of patients with improved symptoms of Heart Failure as assessed by Patient Global Assessment (PGA)

Top of page

End point title

Proportion of patients with improved symptoms of Heart Failure as assessed by Patient Global Assessment (PGA)

End point description

End point type

Secondary

End point timeframe

Week 4, Week 8, Week 12

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: Participants
number (not applicable)
Week 4\|Improvement	176	131
Week 8\|Improvement	190	179
Week 12\|Improvement	189	181
Week 4\|Is unchanged	98	131
Week 8\|Is unchanged	82	88
Week 12\|Is unchanged	79	94
Week 4\|Gets worse	17	21
Week 8\|Gets worse	16	15
Week 12\|Gets worse	19	12
Week 4\|Missing	11	19
Week 8\|Missing	14	20
Week 12\|Missing	15	15

Week 4

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0029

Method

Chi-squared

Confidence interval

Week 8

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7754

Method

Chi-squared

Confidence interval

Week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2172

Method

Chi-squared

Confidence interval

Secondary: Change from Baseline in mean daily non-sedentary daytime activity in weekly intervals

Top of page

End point title

Change from Baseline in mean daily non-sedentary daytime activity in weekly intervals

End point description

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

End point type

Secondary

End point 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

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: minutes
arithmetic mean (standard deviation)
Baseline	512.07 ± 126.37	505.31 ± 129.74
Week 1	527.34 ± 129.54	509.28 ± 131.75
Change from BL at Week 1	22.60 ± 62.33	9.88 ± 50.17
Week 2	351.19 ± 133.89	508.70 ± 133.69
Change from BL at Week 2	22.80 ± 70.25	6.19 ± 55.14
Week 3	525.98 ± 126.66	513.63 ± 130.58
Change from BL at Week 3	13.55 ± 66.74	6.40 ± 62.63
Week 4	519.43 ± 133.21	503.25 ± 139.48
Change from BL at Week 4	11.99 ± 60.10	-5.35 ± 72.35
Week 5	507.46 ± 129.31	501.70 ± 138.12
Change from BL at Week 5	1.77 ± 71.74	-10.95 ± 81.39
Week 6	504.15 ± 131.05	500.39 ± 136.08
Change from BL at Week 6	-0.44 ± 76.32	-7.91 ± 69.71
Week 7	495.06 ± 127.80	503.46 ± 136.69
Change from BL at Week 7	-10.35 ± 76.94	-6.54 ± 75.77
Week 8	497.62 ± 130.56	496.45 ± 139.12
Change from BL at Week 8	-9.49 ± 79.10	-9.21 ± 75.23
Week 9	496.74 ± 128.90	497.24 ± 131.02
Change from BL at Week 9	-10.09 ± 69.93	-10.75 ± 75.82
Week 10	495.53 ± 130.97	500.88 ± 138.35
Change from BL at Week 10	-9.46 ± 80.47	-7.52 ± 77.12
Week 11	492.28 ± 127.19	495.14 ± 135.54
Change from BL at Week 11	-12.93 ± 74.12	-11.64 ± 75.35
Week 12	492.28 ± 127.19	495.14 ± 135.54
Change from BL at Week 12	-12.93 ± 74.12	-11.64 ± 75.35

Change from BL at Week 1

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0008

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 2

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0008

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 3

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0297

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 4

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0069

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 5

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2275

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 6

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3486

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 9

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5301

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 8

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7184

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 7

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.68

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 10

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6019

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 11

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8229

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8229

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Change from Baseline in mean daily non-sedentary daytime activity in two-weekly intervals

Top of page

End point title

Change from Baseline in mean daily non-sedentary daytime activity in two-weekly intervals

End point description

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

End point type

Secondary

End point 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

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: minutes
arithmetic mean (standard deviation)
Baseline	512.07 ± 126.37	505.31 ± 129.74
Weeks 0 to 2	529.63 ± 129.31	509.02 ± 129.97
Change from BL at Week 2	22.88 ± 60.90	8.06 ± 45.65
Weeks 2 to 4	522.30 ± 126.68	508.57 ± 131.41
Change from BL at Week 4	12.04 ± 54.84	0.55 ± 60.23
Weeks 4 to 6	505.54 ± 127.40	500.49 ± 135.70
Change from BL at Week 6	0.21 ± 68.47	-10.86 ± 72.76
Weeks 6 to 8	495.94 ± 124.78	500.92 ± 135.26
Change from BL at Week 8	-10.11 ± 71.75	-7.62 ± 69.96
Weeks 8 to 10	496.57 ± 126.68	497.02 ± 132.96
Change from BL at Week 10	-8.44 ± 68.35	-8.75 ± 71.50
Weeks 10 to 12	483.20 ± 121.43	493.41 ± 130.00
Change from BL at Week 12	-21.17 ± 68.77	-13.93 ± 72.65

Change from BL at Week 2

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 4

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0123

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 6

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.256

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 8

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5865

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 10

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5463

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3212

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Change from Baseline in mean daily Light non-sedentary daytime physical activity

Top of page

End point title

Change from Baseline in mean daily Light non-sedentary daytime physical activity

End point description

The average number of minutes per day spent in light non-sedentary physical activity was being calculated over 14 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.

End point type

Secondary

End point 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

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: minutes
arithmetic mean (standard deviation)
Baseline	251.94 ± 50.54	247.30 ± 58.70
Week 1	263.17 ± 55.85	251.37 ± 58.13
Change from BL at Week 1	14.10 ± 31.15	6.28 ± 27.98
Week 2	262.42 ± 55.12	248.33 ± 57.81
Change from BL at Week 2	10.91 ± 36.10	1.58 ± 28.80
Week 3	261.80 ± 52.68	251.12 ± 57.48
Change from BL at Week 3	9.68 ± 33.10	3.61 ± 31.85
Week 4	256.10 ± 52.61	246.97 ± 58.06
Change from BL at Week 4	5.14 ± 31.12	-1.77 ± 33.49
Week 5	253.98 ± 54.75	243.71 ± 59.17
Change from BL at Week 5	2.71 ± 37.90	-5.77 ± 37.14
Week 6	252.10 ± 56.73	244.25 ± 57.33
Change from BL at Week 6	1.08 ± 38.80	-4.72 ± 36.44
Week 7	251.02 ± 52.09	244.85 ± 57.32
Change from BL at Week 7	-0.88 ± 38.88	-3.18 ± 37.27
Week 8	251.46 ± 52.21	245.02 ± 59.31
Change from BL at Week 8	-1.71 ± 38.69	-2.41 ± 36.53
Week 9	250.04 ± 52.64	245.84 ± 56.31
Change from BL at Week 9	-2.54 ± 35.74	-4.52 ± 37.14
Week 10	248.33 ± 54.44	245.62 ± 58.69
Change from BL at Week 10	-3.43 ± 42.11	-2.65 ± 36.76
Week 11	248.19 ± 53.09	244.83 ± 59.77
Change from BL at Week 11	-3.86 ± 39.67	-3.13 ± 34.23
Week 12	239.30 ± 52.76	243.63 ± 56.92
Change from BL at Week 12	-11.98 ± 42.07	-6.55 ± 35.79

Change from BL at Week 1

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0004

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 2

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0009

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 3

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0094

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 4

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0301

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 5

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1557

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 6

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6461

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 8

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3941

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 7

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9759

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 9

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7209

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 11

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7247

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 10

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4444

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2933

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Change from Baseline in mean daily Moderate-to-Vigorous non-sedentary daytime physical activity

Top of page

End point title

Change from Baseline in mean daily Moderate-to-Vigorous non-sedentary daytime physical activity

End point description

The average number of minutes per day spent in moderate to vigorous non-sedentary physical activity was being calculated over 14 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.

End point type

Secondary

End point 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

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: minutes
arithmetic mean (standard deviation)
Baseline	260.13 ± 110.94	258.01 ± 111.73
Week 1	264.16 ± 109.31	257.92 ± 111.47
Change from BL at Week 1	8.50 ± 45.86	3.60 ± 39.79
Week 2	268.77 ± 114.83	260.37 ± 116.00
Change from BL at Week 2	11.89 ± 50.98	4.61 ± 45.53
Week 3	264.19 ± 108.10	262.51 ± 111.15
Change from BL at Week 3	3.87 ± 49.53	2.80 ± 51.23
Week 4	263.35 ± 114.86	256.28 ± 115.82
Change from BL at Week 4	6.85 ± 43.45	-3.58 ± 56.76
Week 5	253.48 ± 108.52	257.99 ± 115.65
Change from BL at Week 5	-0.93 ± 51.57	-5.18 ± 66.01
Week 6	252.05 ± 108.75	256.14 ± 115.35
Change from BL at Week 6	-1.52 ± 55.23	-3.19 ± 54.72
Week 7	244.04 ± 105.32	258.61 ± 118.51
Change from BL at Week 7	-9.47 ± 57.67	-3.35 ± 56.28
Week 8	246.16 ± 109.03	251.42 ± 113.84
Change from BL at Week 8	-7.78 ± 57.13	-6.80 ± 57.90
Week 9	246.70 ± 106.78	251.40 ± 108.51
Change from BL at Week 9	-7.55 ± 54.98	-6.23 ± 57.68
Week 10	247.20 ± 107.41	255.26 ± 116.88
Change from BL at Week 10	-6.03 ± 57.08	-4.86 ± 59.50
Week 11	244.09 ± 104.33	250.31 ± 113.81
Change from BL at Week 11	-9.57 ± 51.95	-8.51 ± 61.45
Week 12	237.15 ± 100.32	248.08 ± 113.51
Change from BL at Week 12	-20.52 ± 58.37	-11.57 ± 64.90

Change from BL at Week 1

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0854

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 2

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0528

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 3

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4137

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 4

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0082

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 5

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7908

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 6

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6499

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 7

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5547

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 8

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6961

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 9

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5946

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 10

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8957

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 11

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8468

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1711

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Total weekly time spent in non-sedentary daytime physical activity

Top of page

End point title

Total weekly time spent in non-sedentary daytime physical activity

End point description

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.

End point type

Secondary

End point 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

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: minutes
arithmetic mean (standard deviation)
Baseline	3616.87 ± 964.92	3528.56 ± 993.10
Week 1	3676.46 ± 923.85	3560.10 ± 916.16
Change from BL at Week 1	103.29 ± 509.20	82.48 ± 588.19
Week 2	3691.24 ± 953.03	3557.71 ± 940.60
Change from BL at Week 2	76.23 ± 563.79	52.38 ± 600.08
Week 3	3668.25 ± 894.91	3580.54 ± 922.70
Change from BL at Week 3	25.28 ± 571.36	34.56 ± 663.68
Week 4	3608.39 ± 936.87	3482.15 ± 991.15
Change from BL at Week 4	5.10 ± 497.55	-56.23 ± 748.35
Week 5	3488.43 ± 944.87	3458.65 ± 973.75
Change from BL at Week 5	-116.74 ± 607.31	-79.18 ± 817.71
Week 6	3519.12 ± 922.58	3489.15 ± 962.55
Change from BL at Week 6	-72.08 ± 569.61	-21.73 ± 724.96
Week 7	3444.52 ± 892.15	3502.67 ± 977.43
Change from BL at Week 7	-143.38 ± 605.25	-36.18 ± 709.43
Week 8	3466.82 ± 936.51	3457.74 ± 993.56
Change from BL at Week 8	-130.59 ± 631.30	-59.92 ± 716.74
Week 9	3470.69 ± 913.06	3447.28 ± 932.67
Change from BL at Week 9	-131.08 ± 549.54	-108.48 ± 719.58
Week 10	3444.77 ± 947.18	3489.68 ± 964.08
Change from BL at Week 10	-119.41 ± 648.17	-68.93 ± 711.22
Week 11	3406.56 ± 910.84	3436.96 ± 971.78
Change from BL at Week 11	-170.14 ± 632.53	-120.35 ± 707.11
Week 12	3093.96 ± 913.14	3234.90 ± 991.50
Change from BL at Week 12	-506.82 ± 792.71	-339.15 ± 786.06

Change from BL at Week 1

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0065

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 2

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0316

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 3

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1342

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 4

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0252

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 5

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9024

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 6

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9052

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 8

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3174

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 7

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.287

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 9

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.502

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 11

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4823

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 10

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4037

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.109

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Total weekly time spent in Light non-sedentary daytime physical activity

Top of page

End point title

Total weekly time spent in Light non-sedentary daytime physical activity

End point description

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.

End point type

Secondary

End point 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

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: minutes
arithmetic mean (standard deviation)
Baseline	1773.14 ± 392.22	1721.50 ± 452.26
Week 1	1834.71 ± 400.46	1757.76 ± 407.14
Change from BL at Week 1	81.84 ± 255.91	53.74 ± 282.22
Week 2	1823.86 ± 396.55	1736.64 ± 407.45
Change from BL at Week 2	46.26 ± 301.74	17.26 ± 280.12
Week 3	1826.38 ± 376.72	1751.95 ± 410.11
Change from BL at Week 3	46.05 ± 281.11	24.88 ± 313.52
Week 4	1778.88 ± 372.86	1707.68 ± 410.73
Change from BL at Week 4	9.17 ± 275.92	-18.74 ± 346.02
Week 5	1745.87 ± 406.21	1683.08 ± 429.50
Change from BL at Week 5	-36.66 ± 307.01	-37.98 ± 369.53
Week 6	1759.09 ± 397.67	1701.89 ± 405.01
Change from BL at Week 6	-17.85 ± 290.75	-16.56 ± 343.51
Week 7	1747.03 ± 366.43	1702.58 ± 399.11
Change from BL at Week 7	-32.03 ± 307.16	-17.71 ± 322.33
Week 8	1750.02 ± 377.35	1705.09 ± 424.99
Change from BL at Week 8	-37.50 ± 323.19	-17.49 ± 318.83
Week 9	1746.73 ± 375.07	1706.26 ± 407.89
Change from BL at Week 9	-36.47 ± 289.67	-43.21 ± 341.30
Week 10	1724.72 ± 395.95	1712.55 ± 412.82
Change from BL at Week 10	-46.95 ± 339.81	-22.01 ± 314.65
Week 11	1717.08 ± 386.33	1697.81 ± 429.44
Change from BL at Week 11	-60.08 ± 319.85	-40.52 ± 313.76
Week 12	1559.62 ± 428.02	1607.33 ± 449.83
Change from BL at Week 12	-210.49 ± 390.17	-144.96 ± 339.29

Change from BL at Week 2

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0143

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 1

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0061

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 3

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0708

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 5

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8017

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 4

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.075

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 6

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7956

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 7

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3499

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 8

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1192

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 9

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5237

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 10

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3902

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 11

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4228

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1571

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Total weekly time spent in Moderate-to-Vigorous non-sedentary daytime physical activity

Top of page

End point title

Total weekly time spent in Moderate-to-Vigorous non-sedentary daytime physical activity

End point description

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.

End point type

Secondary

End point 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

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: minutes
arithmetic mean (standard deviation)
Baseline	1843.73 ± 830.30	1807.07 ± 815.89
Week 1	1841.76 ± 769.54	1802.34 ± 775.36
Change from BL at Week 1	21.45 ± 373.16	28.75 ± 404.20
Week 2	1867.37 ± 806.56	1821.07 ± 813.27
Change from BL at Week 2	29.97 ± 383.31	35.13 ± 432.43
Week 3	1841.87 ± 755.88	1828.59 ± 777.65
Change from BL at Week 3	-20.77 ± 425.19	9.68 ± 458.99
Week 4	1829.51 ± 801.93	1774.46 ± 815.93
Change from BL at Week 4	-4.07 ± 344.29	-37.49 ± 506.27
Week 5	1742.56 ± 767.53	1775.57 ± 798.92
Change from BL at Week 5	-80.08 ± 423.07	-41.20 ± 577.49
Week 6	1760.03 ± 763.64	1787.26 ± 810.30
Change from BL at Week 6	-54.23 ± 416.05	-5.17 ± 509.74
Week 7	1697.49 ± 732.18	1800.09 ± 829.37
Change from BL at Week 7	-111.35 ± 438.85	-18.47 ± 505.11
Week 8	1716.80 ± 769.31	1752.65 ± 802.46
Change from BL at Week 8	-93.09 ± 429.65	-42.43 ± 522.80
Week 9	1723.96 ± 750.60	1741.02 ± 757.26
Change from BL at Week 9	-94.81 ± 407.63	-65.27 ± 492.38
Week 10	1720.06 ± 760.72	1777.14 ± 811.27
Change from BL at Week 10	-72.46 ± 442.80	-45.92 ± 514.49
Week 11	1689.48 ± 731.77	1739.15 ± 803.36
Change from BL at Week 11	-110.06 ± 432.47	-79.83 ± 516.05
Week 12	1534.35 ± 678.12	1627.57 ± 778.70
Change from BL at Week 12	-296.33 ± 525.81	-194.19 ± 564.53

Change from BL at Week 1

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3231

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 2

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3519

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 3

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8335

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 4

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0465

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 5

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5016

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 6

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5941

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 8

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4125

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 7

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2019

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 9

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5702

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 11

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5343

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 10

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4752

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0985

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Change from Baseline in peak six minutes of daytime physical activity

Top of page

End point title

Change from Baseline in peak six minutes of daytime physical activity

End point description

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.

End point type

Secondary

End point timeframe

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

End point values	LCZ696 (Sacubitril/Valsartan)	Enalapril
Number of subjects analysed	302	302
Units: minutes
arithmetic mean (standard deviation)
Baseline	189.08 ± 76.75	182.52 ± 60.09
Week 2	193.54 ± 77.30	184.46 ± 59.49
Change from BL at Week 2	6.18 ± 46.72	3.52 ± 32.16
Week 4	191.86 ± 80.21	181.11 ± 61.75
Change from BL at Week 4	5.47 ± 50.93	-0.23 ± 40.44
Week 6	191.21 ± 77.38	181.11 ± 55.07
Change from BL at Week 6	2.69 ± 42.51	-1.02 ± 38.82
Week 8	183.96 ± 70.54	180.92 ± 57.28
Change from BL at Week 8	-2.71 ± 41.43	-0.22 ± 38.05
Week 12	184.42 ± 67.09	180.44 ± 55.36
Change from BL at Week 12	-1.07 ± 49.32	-2.45 ± 39.15

Change from BL at Week 2

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4525

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 4

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0445

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 6

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1158

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 8

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3901

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Change from BL at Week 12

Comparison groups

LCZ696 (Sacubitril/Valsartan) v Enalapril

Number of subjects included in analysis

604

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7725

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse Events were collected for the maximum duration of participants's treatment exposure plus any follow up period, approximately 4 months.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Enalapril

Reporting group description

Enalapril

Reporting group title

Sacubitril/valsartan

Reporting group description

Sacubitril/valsartan

Serious adverse events	Enalapril	Sacubitril/valsartan
Total subjects affected by serious adverse events
subjects affected / exposed	28 / 310 (9.03%)	19 / 309 (6.15%)
number of deaths (all causes)	4	1
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastatic bronchial carcinoma
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Intermittent claudication
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Renal lithiasis prophylaxis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pyrexia
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Prostatitis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Injury, poisoning and procedural complications
Coronary bypass thrombosis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	2 / 310 (0.65%)	4 / 309 (1.29%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 1
Atrial flutter
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Cardiac failure
subjects affected / exposed	7 / 310 (2.26%)	4 / 309 (1.29%)
occurrences causally related to treatment / all	1 / 7	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 1
Cardiac failure congestive
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Paraesthesia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stroke in evolution
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin necrosis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urogenital haemorrhage
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Diverticulitis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Enalapril	Sacubitril/valsartan
Total subjects affected by non serious adverse events
subjects affected / exposed	143 / 310 (46.13%)	168 / 309 (54.37%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Monoclonal gammopathy
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Vascular disorders
Blood pressure fluctuation
subjects affected / exposed	2 / 310 (0.65%)	1 / 309 (0.32%)
occurrences all number	2	1
Haematoma
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Circulatory collapse
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Hypertension
subjects affected / exposed	1 / 310 (0.32%)	2 / 309 (0.65%)
occurrences all number	1	2
Hypotension
subjects affected / exposed	20 / 310 (6.45%)	43 / 309 (13.92%)
occurrences all number	20	45
Intermittent claudication
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Orthostatic hypotension
subjects affected / exposed	1 / 310 (0.32%)	3 / 309 (0.97%)
occurrences all number	1	3
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Peripheral coldness
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Surgical and medical procedures
Inguinal hernia repair
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 310 (0.97%)	1 / 309 (0.32%)
occurrences all number	3	1
Chest pain
subjects affected / exposed	0 / 310 (0.00%)	5 / 309 (1.62%)
occurrences all number	0	5
Chest discomfort
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Fatigue
subjects affected / exposed	6 / 310 (1.94%)	6 / 309 (1.94%)
occurrences all number	7	7
Feeling abnormal
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
General physical health deterioration
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Malaise
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences all number	0	2
Mucosal dryness
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Oedema
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Oedema peripheral
subjects affected / exposed	3 / 310 (0.97%)	5 / 309 (1.62%)
occurrences all number	3	6
Pain
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Pyrexia
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Swelling
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Seasonal allergy
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Ovarian cyst
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences all number	2	0
Cough
subjects affected / exposed	10 / 310 (3.23%)	10 / 309 (3.24%)
occurrences all number	10	10
Dyspnoea
subjects affected / exposed	9 / 310 (2.90%)	10 / 309 (3.24%)
occurrences all number	10	11
Dysphonia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Dyspnoea exertional
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Emphysema
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Dyspnoea paroxysmal nocturnal
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Obstructive airways disorder
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Lung disorder
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	2
Oropharyngeal pain
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Productive cough
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences all number	2	0
Pulmonary hypertension
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Throat irritation
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Libido decreased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Insomnia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Psychotic disorder
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Restlessness
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Sleep disorder
subjects affected / exposed	2 / 310 (0.65%)	2 / 309 (0.65%)
occurrences all number	2	2
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Blood 25-hydroxycholecalciferol decreased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Blood creatinine increased
subjects affected / exposed	5 / 310 (1.61%)	6 / 309 (1.94%)
occurrences all number	5	6
Blood potassium decreased
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Blood potassium increased
subjects affected / exposed	4 / 310 (1.29%)	4 / 309 (1.29%)
occurrences all number	4	4
Blood pressure ambulatory decreased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Blood pressure decreased
subjects affected / exposed	0 / 310 (0.00%)	3 / 309 (0.97%)
occurrences all number	0	3
Blood pressure increased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
C-reactive protein increased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Glomerular filtration rate decreased
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences all number	0	2
Glomerular filtration rate increased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Heart rate decreased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Heart rate increased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Hepatic enzyme increased
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences all number	0	2
Laboratory test abnormal
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Liver function test increased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Platelet count increased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Red blood cell sedimentation rate increased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Weight decreased
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
White blood cell count increased
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Contusion
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	2
Drug dispensing error
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Foreign body
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Fall
subjects affected / exposed	5 / 310 (1.61%)	1 / 309 (0.32%)
occurrences all number	5	1
Hand fracture
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Injury
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Joint injury
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Laceration
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Muscle strain
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Limb injury
subjects affected / exposed	2 / 310 (0.65%)	2 / 309 (0.65%)
occurrences all number	2	2
Pelvic fracture
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Skin abrasion
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Underdose
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Atrial fibrillation
subjects affected / exposed	2 / 310 (0.65%)	4 / 309 (1.29%)
occurrences all number	2	4
Atrial flutter
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Bradycardia
subjects affected / exposed	3 / 310 (0.97%)	2 / 309 (0.65%)
occurrences all number	3	2
Cardiac failure
subjects affected / exposed	11 / 310 (3.55%)	7 / 309 (2.27%)
occurrences all number	11	8
Cardiac failure chronic
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Cardiovascular insufficiency
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Left ventricular dysfunction
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Palpitations
subjects affected / exposed	2 / 310 (0.65%)	3 / 309 (0.97%)
occurrences all number	2	4
Sinus bradycardia
subjects affected / exposed	2 / 310 (0.65%)	1 / 309 (0.32%)
occurrences all number	3	1
Sinus tachycardia
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Supraventricular tachycardia
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Tachycardia
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences all number	3	0
Ventricular fibrillation
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Ventricular tachycardia
subjects affected / exposed	1 / 310 (0.32%)	3 / 309 (0.97%)
occurrences all number	1	3
Nervous system disorders
Ageusia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Carpal tunnel syndrome
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Cervicobrachial syndrome
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Dementia Alzheimer's type
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Dizziness
subjects affected / exposed	10 / 310 (3.23%)	17 / 309 (5.50%)
occurrences all number	11	20
Dizziness postural
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences all number	0	2
Headache
subjects affected / exposed	4 / 310 (1.29%)	2 / 309 (0.65%)
occurrences all number	4	2
Lethargy
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Hypotonia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Presyncope
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Migraine
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	3
Radiculopathy
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Sciatica
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	2
Somnolence
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Syncope
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 310 (0.65%)	2 / 309 (0.65%)
occurrences all number	2	2
Iron deficiency anaemia
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Lymphadenopathy
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Ear and labyrinth disorders
Otorrhoea
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Tinnitus
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Vertigo
subjects affected / exposed	1 / 310 (0.32%)	2 / 309 (0.65%)
occurrences all number	1	2
Eye disorders
Blepharitis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Cataract
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Glaucoma
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Retinal vein occlusion
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Vision blurred
subjects affected / exposed	0 / 310 (0.00%)	3 / 309 (0.97%)
occurrences all number	0	3
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Abdominal pain
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Abdominal pain upper
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Aerophagia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Chronic gastritis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Constipation
subjects affected / exposed	1 / 310 (0.32%)	2 / 309 (0.65%)
occurrences all number	1	2
Diarrhoea
subjects affected / exposed	6 / 310 (1.94%)	8 / 309 (2.59%)
occurrences all number	6	10
Dry mouth
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Dyspepsia
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences all number	0	3
Dysphagia
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Epigastric discomfort
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Flatulence
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Gastritis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Haemorrhoidal haemorrhage
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Irritable bowel syndrome
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Large intestine polyp
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Nausea
subjects affected / exposed	2 / 310 (0.65%)	3 / 309 (0.97%)
occurrences all number	2	3
Odynophagia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Rectal ulcer
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Salivary hypersecretion
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Alopecia
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences all number	0	2
Angioedema
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Blister
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Dry skin
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Ecchymosis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Eczema
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Hair texture abnormal
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Hyperhidrosis
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences all number	2	0
Madarosis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Pruritus
subjects affected / exposed	0 / 310 (0.00%)	4 / 309 (1.29%)
occurrences all number	0	4
Rash
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences all number	0	2
Skin ulcer
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Urticaria
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Bladder neck obstruction
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Haematuria
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Nocturia
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Renal colic
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Pollakiuria
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Renal disorder
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Renal impairment
subjects affected / exposed	3 / 310 (0.97%)	4 / 309 (1.29%)
occurrences all number	3	4
Renal failure
subjects affected / exposed	0 / 310 (0.00%)	4 / 309 (1.29%)
occurrences all number	0	5
Renal pain
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Hypothyroidism
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	6 / 310 (1.94%)	4 / 309 (1.29%)
occurrences all number	6	5
Back pain
subjects affected / exposed	9 / 310 (2.90%)	6 / 309 (1.94%)
occurrences all number	9	7
Intervertebral disc degeneration
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Limb discomfort
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Mobility decreased
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Muscle spasms
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Musculoskeletal pain
subjects affected / exposed	3 / 310 (0.97%)	1 / 309 (0.32%)
occurrences all number	3	1
Myalgia
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Neck pain
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Osteoarthritis
subjects affected / exposed	1 / 310 (0.32%)	2 / 309 (0.65%)
occurrences all number	1	2
Osteochondrosis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Osteopenia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Pain in extremity
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences all number	2	0
Rheumatoid arthritis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Spinal column stenosis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Spinal osteoarthritis
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences all number	2	0
Spinal pain
subjects affected / exposed	0 / 310 (0.00%)	3 / 309 (0.97%)
occurrences all number	0	3
Tendon pain
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Tendonitis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 310 (0.65%)	6 / 309 (1.94%)
occurrences all number	2	7
Campylobacter gastroenteritis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Cellulitis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Chlamydial infection
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Conjunctivitis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Ear infection
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Folliculitis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Gastroenteritis
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences all number	2	0
Herpes simplex
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Herpes zoster
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Influenza
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Lower respiratory tract infection
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Nasopharyngitis
subjects affected / exposed	8 / 310 (2.58%)	8 / 309 (2.59%)
occurrences all number	8	8
Oesophageal candidiasis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Oral herpes
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Pharyngitis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Pneumonia
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Pyelonephritis acute
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Respiratory tract infection
subjects affected / exposed	2 / 310 (0.65%)	1 / 309 (0.32%)
occurrences all number	2	1
Rhinitis
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Sinusitis
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences all number	0	2
Tracheobronchitis
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Upper respiratory tract infection
subjects affected / exposed	2 / 310 (0.65%)	0 / 309 (0.00%)
occurrences all number	2	0
Urinary tract infection
subjects affected / exposed	3 / 310 (0.97%)	3 / 309 (0.97%)
occurrences all number	3	3
Viral infection
subjects affected / exposed	1 / 310 (0.32%)	3 / 309 (0.97%)
occurrences all number	1	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 310 (0.65%)	1 / 309 (0.32%)
occurrences all number	2	1
Dehydration
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences all number	0	2
Diabetes mellitus
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 310 (0.32%)	0 / 309 (0.00%)
occurrences all number	1	0
Gout
subjects affected / exposed	1 / 310 (0.32%)	3 / 309 (0.97%)
occurrences all number	1	3
Hypercalcaemia
subjects affected / exposed	0 / 310 (0.00%)	2 / 309 (0.65%)
occurrences all number	0	3
Hyperkalaemia
subjects affected / exposed	11 / 310 (3.55%)	22 / 309 (7.12%)
occurrences all number	11	22
Hyperuricaemia
subjects affected / exposed	1 / 310 (0.32%)	1 / 309 (0.32%)
occurrences all number	1	1
Hyponatraemia
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1
Iron deficiency
subjects affected / exposed	0 / 310 (0.00%)	1 / 309 (0.32%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

26 Oct 2016

Amendment 1, issued before trial initiation, was introduced as a consequence of feedback and specific requirements from Health Authorities. In summary, these requirements were put in place to detail the potential risk of interaction between specific antidiabetic medication and both the comparator and investigational medicinal product. Furthermore, a precision of specific exclusion criteria were given (26 and 32), by which prohibited concomitant medication and the need for ECG was further specified. In addition, patients eligible for re-screening in the study were further specified as well as further guidance was provided for the eligibility and potential use of the unscheduled visits between set visits. The alert criteria to kidney function were refined in Appendix 16.1.1-Protocol-Appendix 3 where the urine events were deleted due to redundancy with serum events as well as Appendix 16.1.1-Protocol-Appendix 6. A precision was also added in the hypothetical terms where the study could be terminated.

18 Nov 2016

Amendment 2, issued also before trial initiation, was introduced due to a specific requirement from Health Authorities. The scope of this amendment was to change specific criteria for when patients were found to be eligible for re-screening in this study. Implementation of this amendment increased the precision of patients re-screened and optimized the recruitment of the patients of interest of this study.

02 Feb 2018

Amendment 3, issued when recruitment was complete, was introduced as a consequence to the realization that combining specific visit windows could allow a mismatch in number of days between visits and number of available study drug. In addition, we added a precision to the dosing level ranges to avoid any ambiguity and lastly, an additional method for imputing missing data was added. Implementation of this amendment secured that the study patients had sufficient study drug throughout the study regardless of how their study visits were constructed within the new visit windows given. Additionally, adding a new method for imputing the missing data allowed better utilization of data which was not complete but useful.

11 Apr 2018

Amendment 4 issued on 11-Sep-2018, when recruitment was complete and last patient last visit was achieved (11-Apr-2018) but before data base lock and unblinding the patients. The amendment was introduced as a consequence of new and previously unavailable key data regarding the use of accelerometry as a clinical endpoint in trials concerning HF patients and new positioning from the Committee for Medicinal Products for Human Use (CHMP) at the EMA on the use of 6MWT in HF studies (CHMP, 2017).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A multi-center, prospective, randomized, double-blind study to assess the impact of sacubitril/valsartan vs. enalapril on daily physical activity using a wrist worn actigraphy device in adult chronic heart failure patients

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline (Week 0) in the Six Minute Walk Test (6MWT) at end of Study (Week 12)

Primary: Change from Baseline (Week 0) in the Six Minute Walk Test (6MWT) at end of Study (Week 12)

Primary: Change from Baseline (Week 0) in mean daily non-sedentary daytime activity at end of Study (Week 12)

Primary: Change from Baseline (Week 0) in mean daily non-sedentary daytime activity at end of Study (Week 12)

Secondary: Proportion of patients with improved performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS

Secondary: Proportion of patients with improved performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS

Secondary: Proportion of patients with improved performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS subset without AE/SAE

Secondary: Proportion of patients with improved performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS subset without AE/SAE

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked equal to or less than 300 meters at Baseline - FAS

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked equal to or less than 300 meters at Baseline - FAS

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked equal to or less than 300 meters at Baseline - FAS subset without AE/SAE

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked equal to or less than 300 meters at Baseline - FAS subset without AE/SAE

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked 100-450 meters at Baseline - FAS

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked 100-450 meters at Baseline - FAS

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked 100-450 meters at Baseline - FAS subset without AE/SAE

Secondary: Proportion of patients with improved performance (>= 30 m) in the 6MWT which walked 100-450 meters at Baseline - FAS subset without AE/SAE

Secondary: Change from Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8

Secondary: Change from Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8

Secondary: Proportion of patients who show increased levels (>= 10% increase) of non sedentary daytime physical activity at Week 12 compared to Baseline

Secondary: Proportion of patients who show increased levels (>= 10% increase) of non sedentary daytime physical activity at Week 12 compared to Baseline

Secondary: Proportion of patients achieving PGA Score at Weeks 4, 8 and 12

Secondary: Proportion of patients achieving PGA Score at Weeks 4, 8 and 12

Secondary: Proportion of patients with improved symptoms of Heart Failure as assessed by Patient Global Assessment (PGA)

Secondary: Proportion of patients with improved symptoms of Heart Failure as assessed by Patient Global Assessment (PGA)

Secondary: Change from Baseline in mean daily non-sedentary daytime activity in weekly intervals

Secondary: Change from Baseline in mean daily non-sedentary daytime activity in weekly intervals

Secondary: Change from Baseline in mean daily non-sedentary daytime activity in two-weekly intervals

Secondary: Change from Baseline in mean daily non-sedentary daytime activity in two-weekly intervals

Secondary: Change from Baseline in mean daily Light non-sedentary daytime physical activity

Secondary: Change from Baseline in mean daily Light non-sedentary daytime physical activity

Secondary: Change from Baseline in mean daily Moderate-to-Vigorous non-sedentary daytime physical activity

Secondary: Change from Baseline in mean daily Moderate-to-Vigorous non-sedentary daytime physical activity

Secondary: Total weekly time spent in non-sedentary daytime physical activity

Secondary: Total weekly time spent in non-sedentary daytime physical activity

Secondary: Total weekly time spent in Light non-sedentary daytime physical activity

Secondary: Total weekly time spent in Light non-sedentary daytime physical activity

Secondary: Total weekly time spent in Moderate-to-Vigorous non-sedentary daytime physical activity

Secondary: Total weekly time spent in Moderate-to-Vigorous non-sedentary daytime physical activity

Secondary: Change from Baseline in peak six minutes of daytime physical activity

Secondary: Change from Baseline in peak six minutes of daytime physical activity

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A multi-center, prospective, randomized, double-blind study to assess the impact of sacubitril/valsartan vs. enalapril on daily physical activity using a wrist worn actigraphy device in adult chronic heart failure patients