OUTSTEP-HF: randOmized stUdy Using acceleromeTry to Compare Sacubitril/valsarTan and Enalapril in Patients With Heart Failure

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02900378
• Collaborator: (none)
• Enrollment: 621
• Locations: 119
• Arms: 2
• Actual Duration (Months): 15.7
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this randomized, actively controlled, double-blind study with prospective data collection was to assess differences between sacubitril/valsartan versus enalapril in increasing exercise capacity and non-sedentary physical activity in HFrEF patients. Physical activity was assessed by the 6 minute walk test, and daily physical activity was continuously measured by means of a wrist-worn accelerometry device from 2 weeks before until 12 weeks after start of study therapy (sacubitril/valsartan or enalapril).

Condition or Disease	Intervention/Treatment	Phase
Chronic Heart Failure With Reduced Ejection Fraction	Drug: LCZ696 (Sacubitril/Valsartan); Drug: Placebo of LCZ696 (Sacubitril/Valsartan); Drug: Enalapril; Drug: Placebo of Enalapril	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 621 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Dec 20, 2016
• Actual Primary Completion Date: Apr 11, 2018
• Actual Study Completion Date: Apr 11, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 (Sacubitril/Valsartan) After randomization, patients in this arm received LCZ696 (Sacubitril/Valsartan) twice daily and matching placebo of Enalapril depending on the patient's previous ACEI/ARB dose (enalapril equivalent dose) for 2 weeks. Patients could start study medication at dose level 1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ) or matching placebo bid. After 2 weeks (visit 3) the doses were up-titrated: patients, who started on dose level 2 or 2a received the target dose of study medication (level 3) at this point. After another 2 weeks (visit 4) all patients were to achieve the target dose of 97 mg/103 mg bid LCZ696(sacubitril/valsartan) and matching placebo, provided no safety and tolerability issues arised during uptitration.	Drug: LCZ696 (Sacubitril/Valsartan); LCZ696 (sacubitril/valsartan) was available in 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets; Other Names: LCZ696 ; Drug: Placebo of Enalapril; Placebo of Enalapril was available to match 2.5 mg, 5 mg and 10 mg film-coated tablets; Other Names: Placebo
Active Comparator: Enalapril After randomization, patients in this arm received Enalapril twice daily and matching placebo of LCZ696 (Sacubitril/Valsartan) depending on the patient's previous ACEI/ARB for 2 weeks. Patients could start study medication at dose level 1 or 2a or matching placebo bid. After 2 weeks (visit 3) the doses were up-titrated: patients, who started on dose level 2 or 2a received the target dose of study medication (level 3) at this point. After another 2 weeks (visit 4) all patients were to achieve the target dose of 10 mg bid enalapril and matching placebo, provided no safety and tolerability issues arised during uptitration	Drug: Placebo of LCZ696 (Sacubitril/Valsartan); Placebo of LCZ696 (sacubitril/valsartan) was available to match 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets; Other Names: Placebo ; Drug: Enalapril; Enalapril was available in 2.5 mg, 5 mg and 10 mg film-coated tablets

Outcome Measures

Primary Outcome Measures

1. Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12) [Baseline, Week 12]

   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.

2. Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12) [Baseline, Week 12]

   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).

Secondary Outcome Measures

1. Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS [Baseline, Week 12]

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

2. Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS Subset Without AE/SAE [Baseline, Week 12]

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

3. Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS [Baseline, Week 12]

   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.

4. Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS Subset Without AE/SAE [Baseline, Week 12]

   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.

5. Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS [Baseline, Week 12]

   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 from 100 to 450 meters.

6. Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS Subset Without AE/SAE [Baseline, Week 12]

   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 from 100 to 450 meters.

7. Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8 [Baseline, Week 4 and Week 8]

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

8. Number and Percentage of Participants Who Show Increased Levels (>= 10% Increase) of Non Sedentary Daytime Physical Activity at Week 12 Compared to Baseline [Baseline, Week 12]

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

9. Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12 [Week 4, Week 8, Week 12]

   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.

10. Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA) [Week 4, Week 8, Week 12]

    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. Patients with improved symptoms were categorized as: Improvement, Is unchanged, Gets worse or Missing.

11. Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals [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]

    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.

12. Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals [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]

    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.

13. Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity [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]

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

14. Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity [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]

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

15. Total Weekly Time Spent in Non-sedentary Daytime Physical Activity [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]

    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.

16. Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity [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]

    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.

17. Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity [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]

    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.

18. Change From Baseline in Peak Six Minutes of Daytime Physical Activity [Baseline, Week 2, Week 4, Week 6, Week 8 and Week 12]

    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.

Eligibility Criteria

Criteria

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

Key Inclusion Criteria:

• Written informed consent obtained before any study assessment is performed.

• Ambulatory ≥ 18 years of age with a diagnosis of chronic symptomatic HF (NYHA class ≥

1. with reduced ejection fraction, defined as known LVEF ≤ 40%

AND one of the following two criteria:

• Plasma NT-proBNP level of ≥ 300 pg/mL or BNP ≥ 100 pg/mL (measurement may be recorded no longer than past 12 months) OR

• Confirmation of a heart failure hospitalization last 12 months.

• Patients must be on stable HF medication for at least 4 weeks prior to Week - 2, where the minimal daily dose of current evidence based therapies is equivalent to at least 2.5 mg/d enalapril

• Willingness to wear the accelerometer wristband continuously for the duration of the trial.

• Patients must be living in a setting, allowing them to move about freely and where they are primarily self-responsible for scheduling their sleep and daily activities.

Key Exclusion Criteria:

• History of hypersensitivity to any of the study drugs or their excipients or to drugs of similar chemical classes

• Use of sacubitril/valsartan prior to week - 2.

• Bedridden patients, or patients with significantly impaired/limited physical activity and/or fatigue due to medical conditions other than HF, such as, but not limited to angina (chest pain at exertion), arthritis, gout, peripheral artery occlusive disease, obstructive or restrictive lung disease, malignant disease, neurological disorders (e.g. Parkinson's or Alzheimer's disease, central and peripheral neuroinflammatory and -degenerative disorders or functional central nervous lesions due to hemodynamic or traumatic incidents), injuries (incl. diabetic foot ulcers) or missing limbs

• Patients with palsy, tremor or rigor affecting the non-dominant arm.

• Patients with any skin or other condition of the non-dominant arm that would limit the ability to wear the actigraphy device continuously (24h/day) over 14 weeks.

• Patients fully depending on a mobility support system, e.g. wheelchair, scooter or walker. Patients are allowed to use a cane as long as this is not used with the non-dominant arm.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Edegem	Antwerpen	Belgium	2650
2	Novartis Investigative Site	Dendermonde		Belgium	9200
3	Novartis Investigative Site	Geel		Belgium	2440
4	Novartis Investigative Site	Gent		Belgium	9000
5	Novartis Investigative Site	Turnhout		Belgium	2300
6	Novartis Investigative Site	Pleven		Bulgaria	5800
7	Novartis Investigative Site	Plovdiv		Bulgaria	4000
8	Novartis Investigative Site	Sofia		Bulgaria	1233
9	Novartis Investigative Site	Sofia		Bulgaria	1606
10	Novartis Investigative Site	Sofia		Bulgaria	1709
11	Novartis Investigative Site	Brno	Czech Republic	Czechia	60200
12	Novartis Investigative Site	Chomutov	Czech Republic	Czechia	43001
13	Novartis Investigative Site	Svitavy	Czech Republic	Czechia	568 25
14	Novartis Investigative Site	Most	CZE	Czechia	434 01
15	Novartis Investigative Site	Kolin		Czechia	280 20
16	Novartis Investigative Site	Praha 10		Czechia	106 00
17	Novartis Investigative Site	Praha 5		Czechia	150 00
18	Novartis Investigative Site	Helsingoer		Denmark	DK-3000
19	Novartis Investigative Site	Odense C		Denmark	DK 5000
20	Novartis Investigative Site	Randers		Denmark	8930
21	Novartis Investigative Site	Roskilde		Denmark	4000
22	Novartis Investigative Site	Svendborg		Denmark	5700
23	Novartis Investigative Site	Tallinn		Estonia	10138
24	Novartis Investigative Site	Tallinn		Estonia	13419
25	Novartis Investigative Site	Tartu		Estonia	51014
26	Novartis Investigative Site	Hameenlinna		Finland	13100
27	Novartis Investigative Site	Tampere		Finland	33520
28	Novartis Investigative Site	Auxerre		France	89000
29	Novartis Investigative Site	Clermont-Ferrand Cedex 1		France	63003
30	Novartis Investigative Site	Metz Tessy		France	74370
31	Novartis Investigative Site	Dresden	Sachsen	Germany	01099
32	Novartis Investigative Site	Bad Homburg		Germany	61348
33	Novartis Investigative Site	Berlin		Germany	10787
34	Novartis Investigative Site	Berlin		Germany	10789
35	Novartis Investigative Site	Berlin		Germany	13055
36	Novartis Investigative Site	Berlin		Germany	13353
37	Novartis Investigative Site	Buchholz in der Nordheide		Germany	21244
38	Novartis Investigative Site	Dietzenbach		Germany	63128
39	Novartis Investigative Site	Elsterwerda		Germany	04910
40	Novartis Investigative Site	Essen		Germany	45355
41	Novartis Investigative Site	Frankfurt		Germany	60594
42	Novartis Investigative Site	Halberstadt		Germany	38820
43	Novartis Investigative Site	Hamburg		Germany	22041
44	Novartis Investigative Site	Hassloch		Germany	67454
45	Novartis Investigative Site	Leipzig		Germany	04103
46	Novartis Investigative Site	Loehne		Germany	32584
47	Novartis Investigative Site	Mannheim		Germany	68165
48	Novartis Investigative Site	Muehldorf		Germany	84453
49	Novartis Investigative Site	Nuremberg		Germany	90402
50	Novartis Investigative Site	Reinfeld		Germany	23858
51	Novartis Investigative Site	Schwaebisch Hall		Germany	74523
52	Novartis Investigative Site	Siegen		Germany	57 072
53	Novartis Investigative Site	Wallerfing		Germany	94574
54	Novartis Investigative Site	Wedel		Germany	22880
55	Novartis Investigative Site	Wermsdorf		Germany	04779
56	Novartis Investigative Site	Alexandroupolis	Evros	Greece	681 00
57	Novartis Investigative Site	Voula	GR	Greece	166 73
58	Novartis Investigative Site	Athens		Greece	115 27
59	Novartis Investigative Site	Athens		Greece	151 27
60	Novartis Investigative Site	Heraklion Crete		Greece	711 10
61	Novartis Investigative Site	Kopavogur		Iceland	201
62	Novartis Investigative Site	Reykjavik		Iceland	IS-101
63	Novartis Investigative Site	Dublin 7		Ireland
64	Novartis Investigative Site	Jelgava		Latvia	3001
65	Novartis Investigative Site	Ogre		Latvia	5001
66	Novartis Investigative Site	Riga		Latvia	1012
67	Novartis Investigative Site	Riga		Latvia	LV 1002
68	Novartis Investigative Site	Riga		Latvia	LV-1001
69	Novartis Investigative Site	Kaunas	LTU	Lithuania	LT 50161
70	Novartis Investigative Site	Klaipeda	LTU	Lithuania	LT-92288
71	Novartis Investigative Site	Vilnius		Lithuania	LT-08661
72	Novartis Investigative Site	Goes		Netherlands	4462 RA
73	Novartis Investigative Site	Haarlem		Netherlands	2035 RC
74	Novartis Investigative Site	Heerlen		Netherlands	6419
75	Novartis Investigative Site	Leiderdorp		Netherlands	2353 GA
76	Novartis Investigative Site	Roermond		Netherlands	6043 CV
77	Novartis Investigative Site	Veldhoven		Netherlands	5504 DB
78	Novartis Investigative Site	Feiring		Norway	2093
79	Novartis Investigative Site	Lodz	Lodzkie	Poland	91425
80	Novartis Investigative Site	Warszawa	Mazowieckie	Poland	02-676
81	Novartis Investigative Site	Warszawa		Poland	02-097
82	Novartis Investigative Site	Warszawa		Poland	02-507
83	Novartis Investigative Site	Warszawa		Poland	05077
84	Novartis Investigative Site	Ferrol	A Coruna	Spain	15405
85	Novartis Investigative Site	Elche	Alicante	Spain	03293
86	Novartis Investigative Site	Cordoba	Andalucia	Spain	14004
87	Novartis Investigative Site	Granada	Andalucia	Spain	18014
88	Novartis Investigative Site	Huelva	Andalucia	Spain	21005
89	Novartis Investigative Site	Sanlúcar de Barrameda	Andalucia	Spain	11540
90	Novartis Investigative Site	Sevilla	Andalucia	Spain	41009
91	Novartis Investigative Site	Gijon	Asturias	Spain	33290
92	Novartis Investigative Site	Oviedo	Asturias	Spain	33011
93	Novartis Investigative Site	Villamartin	Cadiz	Spain	11650
94	Novartis Investigative Site	Santander	Cantabria	Spain	39008
95	Novartis Investigative Site	Aranda de Duero	Castilla Y Leon	Spain	09400
96	Novartis Investigative Site	Burgos	Castilla Y Leon	Spain	09006
97	Novartis Investigative Site	Leon	Castilla Y Leon	Spain	24071
98	Novartis Investigative Site	Soria	Castilla Y Leon	Spain	42005
99	Novartis Investigative Site	Sabadell	Cataluña	Spain	08208
100	Novartis Investigative Site	Alicante	Comunidad Valenciana	Spain	03010
101	Novartis Investigative Site	Caceres	Extremadura	Spain	10003
102	Novartis Investigative Site	Lugo	Galicia	Spain	27003
103	Novartis Investigative Site	Santiago de Compostela	Galicia	Spain	15706
104	Novartis Investigative Site	Manises	Valencia	Spain	46940
105	Novartis Investigative Site	Barcelona		Spain	08041
106	Novartis Investigative Site	Girona		Spain	17007
107	Novartis Investigative Site	Madrid		Spain	28031
108	Novartis Investigative Site	Madrid		Spain	28222
109	Novartis Investigative Site	Lund		Sweden	222 21
110	Novartis Investigative Site	Molndal		Sweden	431 80
111	Novartis Investigative Site	Stockholm		Sweden	17176
112	Novartis Investigative Site	Stockton on Tees	Cleveland	United Kingdom	TS19 8PE
113	Novartis Investigative Site	Rothwell	GBR	United Kingdom	NN14 6JQ
114	Novartis Investigative Site	Faringdon	Oxfordshire	United Kingdom	SN7 7YU
115	Novartis Investigative Site	Gateshead	Tyne And Wear	United Kingdom	NE9 6SX
116	Novartis Investigative Site	Bournemouth		United Kingdom	BH7 7DW
117	Novartis Investigative Site	Cumbria		United Kingdom	CA139HT
118	Novartis Investigative Site	Poole		United Kingdom	BH15 2JB
119	Novartis Investigative Site	Wellingborough		United Kingdom	NN8 4RW

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Sep 11, 2018
• Statistical Analysis Plan - Dec 12, 2018

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02900378
• Other Study ID Numbers: CLCZ696B3301; 2016-003085-32
• First Posted: Sep 14, 2016
• Last Update Posted: Sep 2, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Novartis Pharmaceuticals: sacubitril/valsartan; enalapril; physical activity; actigraphy; sleep; heart failure; reduced ejection fraction; randomized controlled trial; accelerometry
• Additional relevant MeSH terms: Heart Failure; Valsartan; Enalapril; Enalaprilat; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

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).
Pre-assignment Detail	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).

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Period Title: Randomization (Visit 2)
STARTED	310	311
COMPLETED	287	283
NOT COMPLETED	23	28
Period Title: Randomization (Visit 2)
STARTED	309	310
Full Analysis Set	302	302
COMPLETED	309	310
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril	Total
Arm/Group 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.	Enalapril or its matching placebo twice a day for 12 weeks. Patients began study treatment (Enalapril) at a specific dose level according to their pre-study ACEI/ARB dose (1 (2.5 mg), 2a (5 mg)) or matching placebo and were up-titrated according to an up-titration scheme.	Total of all reporting groups
Overall Participants	310	311	621
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	67.16 (11.04)	66.62 (10.45)	66.89 (10.74)
Sex: Female, Male (Count of Participants)
Female	71 22.9%	61 19.6%	132 21.3%
Male	238 76.8%	249 80.1%	487 78.4%
Race/Ethnicity, Customized (Number) [Number]
Black or African American	1 0.3%	0 0%	1 0.2%
White	298 96.1%	299 96.1%	597 96.1%
Missing	10 3.2%	11 3.5%	21 3.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at End of Study (Week 12)
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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12 (FAS)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2464
	Comments	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.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Differences of least square means
	Estimated Value	5.68
	Confidence Interval	(2-Sided) 95%; -3.93 to 15.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.89
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12 (FAS without AE/SAE)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0503
	Comments	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.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Differences of least square means
	Estimated Value	8.98
	Confidence Interval	(2-Sided) 97.5%; -1.31 to 19.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.58
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline (Week 0) in Mean Daily Non-sedentary Daytime Activity at End of Study (Week 12)
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).
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12 (FAS with MI)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4769
	Comments	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.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Differences of least square means
	Estimated Value	-6.14
	Confidence Interval	(2-Sided) 97.5%; -25.70 to 13.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.61
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12 (FAS with LOCF)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3463
	Comments	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.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Differences of least square means
	Estimated Value	-5.67
	Confidence Interval	(2-Sided) 95%; -17.48 to 6.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.01
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12 (FAS without MI/LOCF)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3513
	Comments	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.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Differences of least square means
	Estimated Value	-6.24
	Confidence Interval	(2-Sided) 95%; -19.39 to 6.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.69
	Estimation Comments

3. Secondary Outcome

Title	Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS
Description	The proportion of patients with improved performance (>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) was considered.

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
No	142 45.8%	153 49.2%
Yes	149 48.1%	129 41.5%
Missing	11 3.5%	20 6.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	FAS population
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.228
	Confidence Interval	(2-Sided) 95%; 0.882 to 1.708
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number and Percentage of Participants With Improved Performance (>= 30 m) in the Six Minute Walk Test (6MWT) - FAS Subset Without AE/SAE
Description	The proportion of patients with improved performance (>= 30 meters) in the six-minute walk test (6MWT) was assessed by treatment group.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	290	294
No	133 42.9%	146 46.9%
Yes	149 48.1%	129 41.5%
Missing	8 2.6%	19 6.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	FAS subset without AE/SAE
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.251
	Confidence Interval	(2-Sided) 95%; 0.895 to 1.748
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS
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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	78	65
No	35 11.3%	31 10%
Yes	41 13.2%	29 9.3%
Missing	2 0.6%	5 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	FAS population
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.250
	Confidence Interval	(2-Sided) 95%; 0.634 to 2.464
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked Equal to or Less Than 300 Meters at Baseline - FAS Subset Without AE/SAE
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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	75	63
No	33 10.6%	30 9.6%
Yes	41 13.2%	29 9.3%
Missing	1 0.3%	4 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	FAS subset without AE/SAE
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.280
	Confidence Interval	(2-Sided) 95%; 0.644 to 2.544
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS
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 from 100 to 450 meters.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	238	238
No	109 35.2%	121 38.9%
Yes	122 39.4%	105 33.8%
Missing	7 2.3%	12 3.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	FAS population
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.250
	Confidence Interval	(2-Sided) 95%; 0.863 to 1.811
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number and Percentage of Participants With Improved Performance (>= 30 m) in the 6MWT Which Walked 100-450 Meters at Baseline - FAS Subset Without AE/SAE
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 from 100 to 450 meters.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	230	231
No	103 33.2%	115 37%
Yes	122 39.4%	105 33.8%
Missing	5 1.6%	11 3.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	FAS subset without AE/SAE
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.260
	Confidence Interval	(2-Sided) 95%; 0.865 to 1.834
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline (Week 0) in the Six Minute Walk Test (6MWT) at Weeks 4 and 8
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 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.
Time Frame	Baseline, Week 4 and Week 8

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 4 (FAS)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1814
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 4 (FAS without AE/SAE)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3315
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 8 (FAS)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2414
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 8 (FAS without AE/SAE)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1793
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Number and Percentage of Participants Who Show Increased Levels (>= 10% Increase) of Non Sedentary Daytime Physical Activity at Week 12 Compared to Baseline
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 will be calculated over 14 days before randomization (baseline) and the last 14 days of treatment (i.e week 10 to week 12)
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
No	175 56.5%	163 52.4%
Yes	28 9%	31 10%
Missing	99 31.9%	108 34.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Increased levels (>= 10% increase) of non sedentary daytime physical activity at Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.821
	Confidence Interval	(2-Sided) 95%; 0.462 to 1.457
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Number and Percentage of Participants Achieving PGA Score at Weeks 4, 8 and 12
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.
Time Frame	Week 4, Week 8, Week 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
Has much improved	19 6.1%	16 5.1%
Has (moderately) improved	63 20.3%	51 16.4%
Has a little improved	94 30.3%	64 20.6%
Is unchanged	98 31.6%	131 42.1%
Is a little worse	13 4.2%	15 4.8%
Is (moderately) worse	3 1%	5 1.6%
Is much worse	1 0.3%	1 0.3%
Missing	11 3.5%	19 6.1%
Has much improved	23 7.4%	24 7.7%
Has (moderately) improved	79 25.5%	73 23.5%
Has a little improved	88 28.4%	82 26.4%
Is unchanged	82 26.5%	88 28.3%
Is a little worse	14 4.5%	11 3.5%
Is (moderately) worse	2 0.6%	3 1%
Is much worse	0 0%	1 0.3%
Missing	14 4.5%	20 6.4%
Has much improved	35 11.3%	40 12.9%
Has (moderately) improved	72 23.2%	67 21.5%
Has a little improved	82 26.5%	74 23.8%
Is unchanged	79 25.5%	94 30.2%
Is a little worse	12 3.9%	7 2.3%
Is (moderately) worse	5 1.6%	3 1%
Is much worse	2 0.6%	2 0.6%
Missing	15 4.8%	15 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0516
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9025
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6713
	Comments
	Method	Chi-squared
	Comments

12. Secondary Outcome

Title	Number and Percentage of Participants With Improved Symptoms of Heart Failure as Assessed by Patient Global Assessment (PGA)
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. Patients with improved symptoms were categorized as: Improvement, Is unchanged, Gets worse or Missing.
Time Frame	Week 4, Week 8, Week 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
Improvement	176 56.8%	131 42.1%
Is unchanged	98 31.6%	131 42.1%
Gets worse	17 5.5%	21 6.8%
Missing	11 3.5%	19 6.1%
Improvement	190 61.3%	179 57.6%
Is unchanged	82 26.5%	88 28.3%
Gets worse	16 5.2%	15 4.8%
Missing	14 4.5%	20 6.4%
Improvement	189 61%	181 58.2%
Is unchanged	79 25.5%	94 30.2%
Gets worse	19 6.1%	12 3.9%
Missing	15 4.8%	15 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0029
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7754
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2172
	Comments
	Method	Chi-squared
	Comments

13. Secondary Outcome

Title	Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Weekly Intervals
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
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	531.19 (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	519.45 (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 (138.78)
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 (139.69)
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 3
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0297
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0069
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 5
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2275
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3486
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 7
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6800
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7184
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 9
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5301
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 10
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6019
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 11
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8229
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8229
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

14. Secondary Outcome

Title	Change From Baseline in Mean Daily Non-sedentary Daytime Activity in Two-weekly Intervals
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
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 (72.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0123
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2560
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5865
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 10
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5463
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3212
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

15. Secondary Outcome

Title	Change From Baseline in Mean Daily Light Non-sedentary Daytime Physical Activity
Description	The average number of minutes per day spent in light non-sedentary physical activity was being calculated over 7 day epochs. Non-sedentary physical activity is defined as >= 178.5 activity counts per minute and light physical activity is defined as 178.5 - 565.5 counts per minute.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
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)	254.84 (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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 3
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0094
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0301
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 5
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1557
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6461
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 7
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9759
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3941
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 9
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7209
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 10
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4444
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 11
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7247
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2933
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

16. Secondary Outcome

Title	Change From Baseline in Mean Daily Moderate-to-Vigorous Non-sedentary Daytime Physical Activity
Description	The average number of minutes per day spent in moderate to vigorous non-sedentary physical activity was being calculated over 7 day epochs. Non-sedentary physical activity is defined as >= 178.5 activity counts per minute and moderate-to-vigorous activity is defined as > 565.5 counts per minute.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
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	-9.07 (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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0854
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0528
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 3
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4137
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0082
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 5
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7908
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6499
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 7
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5547
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6961
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 9
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5946
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 10
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8957
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 11
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8468
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1711
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

17. Secondary Outcome

Title	Total Weekly Time Spent in Non-sedentary Daytime Physical Activity
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
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	-131.28 (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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0065
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0316
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 3
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1342
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0252
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 5
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9024
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9052
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 7
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2870
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3174
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 9
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5020
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 10
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4037
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 11
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4823
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1090
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

18. Secondary Outcome

Title	Total Weekly Time Spent in Light Non-sedentary Daytime Physical Activity
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0061
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0143
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 3
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0708
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0750
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 5
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8017
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7956
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 7
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3499
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1192
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 9
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5237
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 10
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3902
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 11
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4228
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1571
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

19. Secondary Outcome

Title	Total Weekly Time Spent in Moderate-to-Vigorous Non-sedentary Daytime Physical Activity
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
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)	-46.92 (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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3231
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3519
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 3
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8335
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0465
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 5
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5016
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5941
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 7
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2019
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4125
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 9
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5702
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 10
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4752
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 11
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5343
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0985
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

20. Secondary Outcome

Title	Change From Baseline in Peak Six Minutes of Daytime Physical Activity
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.
Time Frame	Baseline, Week 2, Week 4, Week 6, Week 8 and Week 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set was considered

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Enalapril
Arm/Group 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.	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.
Measure Participants	302	302
Baseline	189.08 (67.75)	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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4525
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0445
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1158
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3901
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Enalapril
	Comments	Change from BL at Week 12
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7725
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 4 months.
Arm/Group Title	LCZ696 (Sacubitril/Valsartan)		Enalapril
Arm/Group 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.		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.
All Cause Mortality
	LCZ696 (Sacubitril/Valsartan)		Enalapril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/309 (0.3%)		4/310 (1.3%)
Serious Adverse Events
	LCZ696 (Sacubitril/Valsartan)		Enalapril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/309 (6.1%)		28/310 (9%)
Blood and lymphatic system disorders
Anaemia	1/309 (0.3%)		0/310 (0%)
Cardiac disorders
Acute coronary syndrome	0/309 (0%)		1/310 (0.3%)
Acute myocardial infarction	0/309 (0%)		1/310 (0.3%)
Angina pectoris	1/309 (0.3%)		0/310 (0%)
Atrial fibrillation	4/309 (1.3%)		2/310 (0.6%)
Atrial flutter	0/309 (0%)		1/310 (0.3%)
Cardiac arrest	0/309 (0%)		2/310 (0.6%)
Cardiac failure	4/309 (1.3%)		7/310 (2.3%)
Cardiac failure congestive	1/309 (0.3%)		0/310 (0%)
Coronary artery disease	1/309 (0.3%)		0/310 (0%)
Myocardial infarction	0/309 (0%)		1/310 (0.3%)
Tachycardia	0/309 (0%)		1/310 (0.3%)
Ventricular arrhythmia	0/309 (0%)		1/310 (0.3%)
Ventricular fibrillation	1/309 (0.3%)		0/310 (0%)
Gastrointestinal disorders
Abdominal pain	0/309 (0%)		1/310 (0.3%)
Gastric haemorrhage	1/309 (0.3%)		0/310 (0%)
Inguinal hernia	0/309 (0%)		1/310 (0.3%)
Intestinal perforation	0/309 (0%)		1/310 (0.3%)
General disorders
Death	0/309 (0%)		1/310 (0.3%)
Pyrexia	0/309 (0%)		2/310 (0.6%)
Infections and infestations
Diverticulitis	0/309 (0%)		1/310 (0.3%)
Epididymitis	1/309 (0.3%)		0/310 (0%)
Pneumonia	0/309 (0%)		2/310 (0.6%)
Respiratory tract infection	1/309 (0.3%)		0/310 (0%)
Sepsis	1/309 (0.3%)		0/310 (0%)
Upper respiratory tract infection	1/309 (0.3%)		0/310 (0%)
Urinary tract infection	1/309 (0.3%)		0/310 (0%)
Injury, poisoning and procedural complications
Coronary bypass thrombosis	0/309 (0%)		1/310 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/309 (0%)		1/310 (0.3%)
Bladder cancer	0/309 (0%)		1/310 (0.3%)
Metastatic bronchial carcinoma	0/309 (0%)		1/310 (0.3%)
Nervous system disorders
Paraesthesia	0/309 (0%)		1/310 (0.3%)
Stroke in evolution	1/309 (0.3%)		0/310 (0%)
Syncope	0/309 (0%)		1/310 (0.3%)
Renal and urinary disorders
Haematuria	0/309 (0%)		1/310 (0.3%)
Renal failure	2/309 (0.6%)		0/310 (0%)
Urinary retention	0/309 (0%)		1/310 (0.3%)
Urogenital haemorrhage	1/309 (0.3%)		0/310 (0%)
Reproductive system and breast disorders
Prostatitis	1/309 (0.3%)		0/310 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/309 (0.3%)		0/310 (0%)
Dyspnoea	0/309 (0%)		1/310 (0.3%)
Respiratory failure	1/309 (0.3%)		1/310 (0.3%)
Skin and subcutaneous tissue disorders
Skin necrosis	0/309 (0%)		1/310 (0.3%)
Surgical and medical procedures
Renal lithiasis prophylaxis	0/309 (0%)		1/310 (0.3%)
Vascular disorders
Intermittent claudication	1/309 (0.3%)		0/310 (0%)
Thrombosis	0/309 (0%)		1/310 (0.3%)
Other (Not Including Serious) Adverse Events
	LCZ696 (Sacubitril/Valsartan)		Enalapril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	168/309 (54.4%)		143/310 (46.1%)
Blood and lymphatic system disorders
Anaemia	2/309 (0.6%)		2/310 (0.6%)
Iron deficiency anaemia	1/309 (0.3%)		0/310 (0%)
Lymphadenopathy	1/309 (0.3%)		0/310 (0%)
Cardiac disorders
Angina pectoris	1/309 (0.3%)		1/310 (0.3%)
Atrial fibrillation	4/309 (1.3%)		2/310 (0.6%)
Atrial flutter	0/309 (0%)		1/310 (0.3%)
Bradycardia	2/309 (0.6%)		3/310 (1%)
Cardiac failure	7/309 (2.3%)		11/310 (3.5%)
Cardiac failure chronic	0/309 (0%)		1/310 (0.3%)
Cardiovascular insufficiency	0/309 (0%)		1/310 (0.3%)
Left ventricular dysfunction	1/309 (0.3%)		0/310 (0%)
Palpitations	3/309 (1%)		2/310 (0.6%)
Sinus bradycardia	1/309 (0.3%)		2/310 (0.6%)
Sinus tachycardia	1/309 (0.3%)		0/310 (0%)
Supraventricular tachycardia	1/309 (0.3%)		1/310 (0.3%)
Tachycardia	0/309 (0%)		2/310 (0.6%)
Ventricular fibrillation	1/309 (0.3%)		0/310 (0%)
Ventricular tachycardia	3/309 (1%)		1/310 (0.3%)
Ear and labyrinth disorders
Otorrhoea	0/309 (0%)		1/310 (0.3%)
Tinnitus	1/309 (0.3%)		0/310 (0%)
Vertigo	2/309 (0.6%)		1/310 (0.3%)
Endocrine disorders
Hyperthyroidism	0/309 (0%)		1/310 (0.3%)
Hypothyroidism	0/309 (0%)		1/310 (0.3%)
Eye disorders
Blepharitis	1/309 (0.3%)		0/310 (0%)
Cataract	1/309 (0.3%)		0/310 (0%)
Glaucoma	0/309 (0%)		1/310 (0.3%)
Retinal vein occlusion	1/309 (0.3%)		0/310 (0%)
Vision blurred	3/309 (1%)		0/310 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/309 (0%)		1/310 (0.3%)
Abdominal pain	1/309 (0.3%)		0/310 (0%)
Abdominal pain upper	1/309 (0.3%)		1/310 (0.3%)
Aerophagia	0/309 (0%)		1/310 (0.3%)
Chronic gastritis	1/309 (0.3%)		0/310 (0%)
Constipation	2/309 (0.6%)		1/310 (0.3%)
Diarrhoea	8/309 (2.6%)		6/310 (1.9%)
Dry mouth	1/309 (0.3%)		0/310 (0%)
Dyspepsia	2/309 (0.6%)		0/310 (0%)
Dysphagia	1/309 (0.3%)		0/310 (0%)
Epigastric discomfort	0/309 (0%)		1/310 (0.3%)
Flatulence	0/309 (0%)		1/310 (0.3%)
Gastritis	0/309 (0%)		1/310 (0.3%)
Gastrooesophageal reflux disease	0/309 (0%)		1/310 (0.3%)
Haemorrhoidal haemorrhage	0/309 (0%)		1/310 (0.3%)
Irritable bowel syndrome	0/309 (0%)		1/310 (0.3%)
Large intestine polyp	1/309 (0.3%)		0/310 (0%)
Nausea	3/309 (1%)		2/310 (0.6%)
Odynophagia	0/309 (0%)		1/310 (0.3%)
Rectal ulcer	0/309 (0%)		1/310 (0.3%)
Salivary hypersecretion	0/309 (0%)		1/310 (0.3%)
General disorders
Asthenia	1/309 (0.3%)		3/310 (1%)
Chest discomfort	1/309 (0.3%)		1/310 (0.3%)
Chest pain	5/309 (1.6%)		0/310 (0%)
Fatigue	6/309 (1.9%)		6/310 (1.9%)
Feeling abnormal	0/309 (0%)		1/310 (0.3%)
General physical health deterioration	0/309 (0%)		1/310 (0.3%)
Malaise	2/309 (0.6%)		0/310 (0%)
Mucosal dryness	1/309 (0.3%)		0/310 (0%)
Non-cardiac chest pain	1/309 (0.3%)		0/310 (0%)
Oedema	0/309 (0%)		1/310 (0.3%)
Oedema peripheral	5/309 (1.6%)		3/310 (1%)
Pain	1/309 (0.3%)		1/310 (0.3%)
Pyrexia	1/309 (0.3%)		0/310 (0%)
Swelling	0/309 (0%)		1/310 (0.3%)
Immune system disorders
Anaphylactic reaction	0/309 (0%)		1/310 (0.3%)
Seasonal allergy	1/309 (0.3%)		0/310 (0%)
Infections and infestations
Bronchitis	6/309 (1.9%)		2/310 (0.6%)
Campylobacter gastroenteritis	1/309 (0.3%)		0/310 (0%)
Cellulitis	0/309 (0%)		1/310 (0.3%)
Chlamydial infection	0/309 (0%)		1/310 (0.3%)
Conjunctivitis	0/309 (0%)		1/310 (0.3%)
Ear infection	1/309 (0.3%)		0/310 (0%)
Folliculitis	1/309 (0.3%)		0/310 (0%)
Gastroenteritis	0/309 (0%)		2/310 (0.6%)
Herpes simplex	0/309 (0%)		1/310 (0.3%)
Herpes zoster	1/309 (0.3%)		1/310 (0.3%)
Influenza	1/309 (0.3%)		1/310 (0.3%)
Lower respiratory tract infection	1/309 (0.3%)		1/310 (0.3%)
Nasopharyngitis	8/309 (2.6%)		8/310 (2.6%)
Oesophageal candidiasis	1/309 (0.3%)		0/310 (0%)
Oral herpes	0/309 (0%)		1/310 (0.3%)
Pharyngitis	0/309 (0%)		1/310 (0.3%)
Pneumonia	0/309 (0%)		1/310 (0.3%)
Pyelonephritis acute	0/309 (0%)		1/310 (0.3%)
Respiratory tract infection	1/309 (0.3%)		2/310 (0.6%)
Rhinitis	0/309 (0%)		1/310 (0.3%)
Sinusitis	2/309 (0.6%)		0/310 (0%)
Tracheobronchitis	1/309 (0.3%)		0/310 (0%)
Upper respiratory tract infection	0/309 (0%)		2/310 (0.6%)
Urinary tract infection	3/309 (1%)		3/310 (1%)
Viral infection	3/309 (1%)		1/310 (0.3%)
Injury, poisoning and procedural complications
Arthropod bite	1/309 (0.3%)		0/310 (0%)
Contusion	1/309 (0.3%)		1/310 (0.3%)
Drug dispensing error	1/309 (0.3%)		0/310 (0%)
Fall	1/309 (0.3%)		5/310 (1.6%)
Foreign body	0/309 (0%)		1/310 (0.3%)
Hand fracture	0/309 (0%)		1/310 (0.3%)
Injury	0/309 (0%)		1/310 (0.3%)
Joint injury	1/309 (0.3%)		1/310 (0.3%)
Laceration	0/309 (0%)		1/310 (0.3%)
Limb injury	2/309 (0.6%)		2/310 (0.6%)
Muscle strain	0/309 (0%)		1/310 (0.3%)
Pelvic fracture	0/309 (0%)		1/310 (0.3%)
Skin abrasion	1/309 (0.3%)		0/310 (0%)
Underdose	0/309 (0%)		1/310 (0.3%)
Investigations
Alanine aminotransferase increased	1/309 (0.3%)		0/310 (0%)
Aspartate aminotransferase increased	1/309 (0.3%)		0/310 (0%)
Blood 25-hydroxycholecalciferol decreased	1/309 (0.3%)		0/310 (0%)
Blood creatinine increased	6/309 (1.9%)		5/310 (1.6%)
Blood potassium decreased	0/309 (0%)		1/310 (0.3%)
Blood potassium increased	4/309 (1.3%)		4/310 (1.3%)
Blood pressure ambulatory decreased	1/309 (0.3%)		0/310 (0%)
Blood pressure decreased	3/309 (1%)		0/310 (0%)
Blood pressure increased	1/309 (0.3%)		0/310 (0%)
C-reactive protein increased	1/309 (0.3%)		0/310 (0%)
Glomerular filtration rate decreased	2/309 (0.6%)		0/310 (0%)
Glomerular filtration rate increased	1/309 (0.3%)		0/310 (0%)
Heart rate decreased	1/309 (0.3%)		0/310 (0%)
Heart rate increased	1/309 (0.3%)		0/310 (0%)
Hepatic enzyme increased	2/309 (0.6%)		0/310 (0%)
Laboratory test abnormal	1/309 (0.3%)		0/310 (0%)
Liver function test increased	1/309 (0.3%)		0/310 (0%)
Platelet count increased	1/309 (0.3%)		0/310 (0%)
Red blood cell sedimentation rate increased	1/309 (0.3%)		0/310 (0%)
Weight decreased	0/309 (0%)		1/310 (0.3%)
White blood cell count increased	1/309 (0.3%)		0/310 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/309 (0.3%)		2/310 (0.6%)
Dehydration	2/309 (0.6%)		0/310 (0%)
Diabetes mellitus	1/309 (0.3%)		0/310 (0%)
Diabetes mellitus inadequate control	0/309 (0%)		1/310 (0.3%)
Gout	3/309 (1%)		1/310 (0.3%)
Hypercalcaemia	2/309 (0.6%)		0/310 (0%)
Hyperkalaemia	22/309 (7.1%)		11/310 (3.5%)
Hyperuricaemia	1/309 (0.3%)		1/310 (0.3%)
Hyponatraemia	1/309 (0.3%)		0/310 (0%)
Iron deficiency	1/309 (0.3%)		0/310 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/309 (1.3%)		6/310 (1.9%)
Back pain	6/309 (1.9%)		9/310 (2.9%)
Intervertebral disc degeneration	1/309 (0.3%)		0/310 (0%)
Limb discomfort	0/309 (0%)		1/310 (0.3%)
Mobility decreased	0/309 (0%)		1/310 (0.3%)
Muscle spasms	0/309 (0%)		1/310 (0.3%)
Musculoskeletal pain	1/309 (0.3%)		3/310 (1%)
Myalgia	1/309 (0.3%)		1/310 (0.3%)
Neck pain	1/309 (0.3%)		0/310 (0%)
Osteoarthritis	2/309 (0.6%)		1/310 (0.3%)
Osteochondrosis	0/309 (0%)		1/310 (0.3%)
Osteopenia	0/309 (0%)		1/310 (0.3%)
Pain in extremity	0/309 (0%)		2/310 (0.6%)
Rheumatoid arthritis	1/309 (0.3%)		0/310 (0%)
Spinal column stenosis	1/309 (0.3%)		0/310 (0%)
Spinal osteoarthritis	0/309 (0%)		2/310 (0.6%)
Spinal pain	3/309 (1%)		0/310 (0%)
Tendon pain	0/309 (0%)		1/310 (0.3%)
Tendonitis	1/309 (0.3%)		0/310 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm	1/309 (0.3%)		0/310 (0%)
Monoclonal gammopathy	1/309 (0.3%)		0/310 (0%)
Nervous system disorders
Ageusia	0/309 (0%)		1/310 (0.3%)
Carpal tunnel syndrome	1/309 (0.3%)		0/310 (0%)
Cervicobrachial syndrome	1/309 (0.3%)		0/310 (0%)
Dementia Alzheimer's type	0/309 (0%)		1/310 (0.3%)
Dizziness	17/309 (5.5%)		10/310 (3.2%)
Dizziness postural	2/309 (0.6%)		0/310 (0%)
Headache	2/309 (0.6%)		4/310 (1.3%)
Hypotonia	0/309 (0%)		1/310 (0.3%)
Lethargy	0/309 (0%)		1/310 (0.3%)
Migraine	1/309 (0.3%)		0/310 (0%)
Presyncope	0/309 (0%)		1/310 (0.3%)
Radiculopathy	0/309 (0%)		1/310 (0.3%)
Sciatica	1/309 (0.3%)		0/310 (0%)
Somnolence	1/309 (0.3%)		0/310 (0%)
Syncope	1/309 (0.3%)		0/310 (0%)
Psychiatric disorders
Anxiety	0/309 (0%)		1/310 (0.3%)
Insomnia	0/309 (0%)		1/310 (0.3%)
Libido decreased	1/309 (0.3%)		0/310 (0%)
Psychotic disorder	1/309 (0.3%)		0/310 (0%)
Restlessness	0/309 (0%)		1/310 (0.3%)
Sleep disorder	2/309 (0.6%)		2/310 (0.6%)
Renal and urinary disorders
Acute kidney injury	0/309 (0%)		1/310 (0.3%)
Bladder neck obstruction	1/309 (0.3%)		0/310 (0%)
Haematuria	1/309 (0.3%)		1/310 (0.3%)
Nocturia	1/309 (0.3%)		0/310 (0%)
Pollakiuria	1/309 (0.3%)		0/310 (0%)
Renal colic	0/309 (0%)		1/310 (0.3%)
Renal disorder	0/309 (0%)		1/310 (0.3%)
Renal failure	4/309 (1.3%)		0/310 (0%)
Renal impairment	4/309 (1.3%)		3/310 (1%)
Renal pain	0/309 (0%)		1/310 (0.3%)
Reproductive system and breast disorders
Breast pain	1/309 (0.3%)		0/310 (0%)
Ovarian cyst	1/309 (0.3%)		0/310 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/309 (0%)		2/310 (0.6%)
Cough	10/309 (3.2%)		10/310 (3.2%)
Dysphonia	0/309 (0%)		1/310 (0.3%)
Dyspnoea	10/309 (3.2%)		9/310 (2.9%)
Dyspnoea exertional	1/309 (0.3%)		0/310 (0%)
Dyspnoea paroxysmal nocturnal	0/309 (0%)		1/310 (0.3%)
Emphysema	0/309 (0%)		1/310 (0.3%)
Lung disorder	1/309 (0.3%)		0/310 (0%)
Obstructive airways disorder	1/309 (0.3%)		0/310 (0%)
Oropharyngeal pain	0/309 (0%)		1/310 (0.3%)
Productive cough	0/309 (0%)		2/310 (0.6%)
Pulmonary hypertension	1/309 (0.3%)		0/310 (0%)
Throat irritation	1/309 (0.3%)		0/310 (0%)
Skin and subcutaneous tissue disorders
Acne	1/309 (0.3%)		0/310 (0%)
Alopecia	2/309 (0.6%)		0/310 (0%)
Angioedema	1/309 (0.3%)		0/310 (0%)
Blister	0/309 (0%)		1/310 (0.3%)
Dry skin	1/309 (0.3%)		0/310 (0%)
Ecchymosis	1/309 (0.3%)		0/310 (0%)
Eczema	0/309 (0%)		1/310 (0.3%)
Hair texture abnormal	1/309 (0.3%)		0/310 (0%)
Hyperhidrosis	0/309 (0%)		2/310 (0.6%)
Madarosis	1/309 (0.3%)		0/310 (0%)
Pruritus	4/309 (1.3%)		0/310 (0%)
Rash	2/309 (0.6%)		0/310 (0%)
Skin ulcer	1/309 (0.3%)		0/310 (0%)
Urticaria	0/309 (0%)		1/310 (0.3%)
Surgical and medical procedures
Inguinal hernia repair	0/309 (0%)		1/310 (0.3%)
Vascular disorders
Blood pressure fluctuation	1/309 (0.3%)		2/310 (0.6%)
Circulatory collapse	1/309 (0.3%)		0/310 (0%)
Haematoma	1/309 (0.3%)		1/310 (0.3%)
Hypertension	2/309 (0.6%)		1/310 (0.3%)
Hypotension	43/309 (13.9%)		20/310 (6.5%)
Intermittent claudication	0/309 (0%)		1/310 (0.3%)
Orthostatic hypotension	3/309 (1%)		1/310 (0.3%)
Peripheral arterial occlusive disease	0/309 (0%)		1/310 (0.3%)
Peripheral coldness	1/309 (0.3%)		0/310 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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