An 8-week Study to Evaluate the Dose Response of AHU377 in Combination With Valsartan 320 mg in Patients With Mild-to-moderate Systolic Hypertension

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01281306
• Collaborator: (none)
• Enrollment: 910
• Locations: 90
• Arms: 7
• Duration (Months): 11
• Patients Per Site: 10.1
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate dose response of blood pressure lowering for 4 doses of AHU377, given once daily (50 mg, 100 mg, 200 mg and 400 mg) in combination with a fixed dose of valsartan (320 mg).

Condition or Disease	Intervention/Treatment	Phase
Systolic Hypertension	Drug: LCZ696; Drug: Valsartan; Drug: AHU377; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 910 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Randomized, Double-blind, Placebo and Active Controlled, Parallel Group Study to Evaluate the Dose Response of AHU377 in Combination With Valsartan 320 mg After 8 Week Treatment in Patients With Mild-to-moderate Systolic Hypertension
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: VAL + AHU 400 mg Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Drug: Valsartan; Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.; Drug: AHU377; AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.
Experimental: VAL + AHU 200 mg Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Drug: Valsartan; Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.; Drug: AHU377; AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.
Experimental: VAL + AHU 100 mg Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Drug: Valsartan; Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.; Drug: AHU377; AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.
Experimental: VAL + AHU 50 mg Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Drug: Valsartan; Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.; Drug: AHU377; AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.
Experimental: VAL 320 mg Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Drug: Valsartan; Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.
Experimental: LCZ 400 mg Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Drug: LCZ696; LCZ696 was supplied as tablets in blister cards in 100 mg strengths.
Experimental: Placebo Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.	Drug: Placebo; Placebo was supplied as tablets in blister cards.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) [Baseline, 8 weeks]

   Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.

Secondary Outcome Measures

1. Change From Baseline in Mean Diastolic Blood Pressure (msDBP) [Baseline, 8 weeks]

   Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.

2. Change From Baseline in Mean 24 Hour Ambulatory SBP (maSBP) and Mean 24 Hour Ambulatory DBP (maDBP) [Baseline, 8 weeks]

   Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.

3. Change From Baseline in Daytime maSBP and maDBP [Baseline, 8 weeks]

   Twenty four hour ABPM was performed twice during the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.

4. Change From Baseline in Nighttime maSBP and maDBP [Baseline and 8 weeks]

   Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.

5. Change From Baseline in Mean Sitting Pulse Pressure [Baseline, 8 weeks]

   Pulse rate measurements were performed. A negative change from baseline indicates improvement.

6. Change From Baseline in Mean Ambulatory Pulse Pressure [Baseline, 8 weeks]

   Pulse rate measurements were performed. A negative change from baseline indicates improvement.

7. Change From Baseline in maSBP and maDBP in Dippers [Baseline, 8 weeks]

   Twenty four hour ABPM was performed twice during the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement.

8. Change From Baseline in maSBP and maDBP in Non-dippers [Baseline, 8 weeks]

   Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement.

9. Change From Baseline in msSBP and msDBP in Participants < 65 Years of Age [Baseline, 8 weeks]

   Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.

10. Change From Baseline in msSBP and msDBP in Participants >= 65 Years of Age [Baseline, 8 weeks]

    Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.

11. Change From Baseline in maSBP and maDBP in Participants < 65 Years of Age [Baseline, 8 weeks]

    Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.

12. Change From Baseline in maSBP and maDBP in Participants >= 65 Years of Age [Baseline, 8 weeks]

    Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.

13. Number of Participants Who Achieved Blood Pressure Control and Blood Pressure Response [8 weeks]

    Sitting BP measurements were performed at trough (23-26 hours post-morning dose). Blood pressure control was defined as msSBP/MSDBP < 140/90 mmHg. Blood pressure response in msSBP was defined as <140 mmHg or a reduction >= 20mmHg from baseline. Blood pressure response in msDBP was defined as < 90 mmHg or a reduction >= 10 mmHg from baseline.

14. Number of Participants With Adverse Events, Serious Adverse Events and Death [8 weeks]

    Adverse event monitoring was conducted throughout the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent must be obtained before any assessment is performed. Patients with mild-to-moderate systolic hypertension, untreated or currently taking antihypertensive therapy.

• Ability to communicate and comply with all study requirements and demonstrate good medication compliance (≥ 80% compliance rate) during the run-in period.

Exclusion Criteria:

• Severe hypertension

• History of angioedema, drug-related or otherwise, as reported by the patient.

• Pregnant or nursing (lactating) women.

• Women of child-bearing potential (WOCBP), UNLESS they are using adequate birth control methods.

• History or evidence of a secondary form of hypertension.

• Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Clearwater	Florida	United States	33756
2	Novartis Investigative Site	Chicago	Illinois	United States	60607
3	Novartis Investigative Site	Chicago	Illinois	United States	60610
4	Novartis Investigative Site	Metairie	Louisiana	United States	70006
5	Novartis Investigative Site	Belzoni	Mississippi	United States	39038
6	Novartis Investigative Site	Jackson	Mississippi	United States	39202
7	Novartis Investigative Site	Jackson	Mississippi	United States	39209
8	Novartis Investigative Site	St. Louis	Missouri	United States	63031
9	Novartis Investigative Site	St. Louis	Missouri	United States	63141
10	Novartis Investigative Site	Henderson	Nevada	United States	89014
11	Novartis Investigative Site	Las Vegas	Nevada	United States	89119
12	Novartis Investigative Site	Buffalo	New York	United States	14215
13	Novartis Investigative Site	Charlotte	North Carolina	United States	28277
14	Novartis Investigative Site	Greensboro	North Carolina	United States	27401
15	Novartis Investigative Site	Greensboro	North Carolina	United States	27408
16	Novartis Investigative Site	Shelby	North Carolina	United States	28152
17	Novartis Investigative Site	Erie	Pennsylvania	United States	16509
18	Novartis Investigative Site	Bryan	Texas	United States	77802
19	Novartis Investigative Site	Houston	Texas	United States	77030
20	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1440AAD
21	Novartis Investigative Site	Lanus	Buenos Aires	Argentina	B8000XAV
22	Novartis Investigative Site	Caba	Capital Federal	Argentina	C1179AAB
23	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000AII
24	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S200CXP
25	Novartis Investigative Site	San Miguel de Tucuman	Tucuman	Argentina	T4000EBR
26	Novartis Investigative Site	Buenos aires		Argentina	C1120AAC
27	Novartis Investigative Site	Cordoba		Argentina	X5003DCP
28	Novartis Investigative Site	Corrientes		Argentina	W3400
29	Novartis Investigative Site	Mount Pearl	Newfoundland and Labrador	Canada	A1N 1W7
30	Novartis Investigative Site	Mirabel	Quebec	Canada	J7J 2K8
31	Novartis Investigative Site	Ste-Foy	Quebec	Canada	G1V 4G2
32	Novartis Investigative Site	Budapest		Hungary	1045
33	Novartis Investigative Site	Budapest		Hungary	1136
34	Novartis Investigative Site	Csongrad		Hungary	6640
35	Novartis Investigative Site	Erd		Hungary	H-2030
36	Novartis Investigative Site	Miskolc		Hungary	3525
37	Novartis Investigative Site	Miskolc		Hungary	3530
38	Novartis Investigative Site	Nyiregyháza		Hungary	4400
39	Novartis Investigative Site	Szeged		Hungary	H-6720
40	Novartis Investigative Site	Torokbalint		Hungary	2045
41	Novartis Investigative Site	Vishakhapatnam	Andhra Pradesh	India	530002
42	Novartis Investigative Site	Ahmedabad	Gujarat	India	380 051
43	Novartis Investigative Site	Nashik	Maharashtra	India	422 005
44	Novartis Investigative Site	Nashik	Maharashtra	India	422005
45	Novartis Investigative Site	Pune	Maharashtra	India	411005
46	Novartis Investigative Site	Ludhiana	Punjab	India	141002
47	Novartis Investigative Site	Jaipur	Rajasthan	India	302016
48	Novartis Investigative Site	Lucknow	Uttar Pradesh	India	226003
49	Novartis Investigative Site	Lucknow	Uttar Pradesh	India	226005
50	Novartis Investigative Site	Bucheon	Gyeonggi-do	Korea, Republic of	424-717
51	Novartis Investigative Site	Goyang	Gyeonggi-do	Korea, Republic of	411-706
52	Novartis Investigative Site	Uijeongbu-Si	Gyeonggi-do	Korea, Republic of	480-717
53	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	05505
54	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	137-701
55	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	152-703
56	Novartis Investigative Site	Koyang	Kyunggi	Korea, Republic of	410-719
57	Novartis Investigative Site	Seoul		Korea, Republic of	140-743
58	Novartis Investigative Site	Seoul		Korea, Republic of	150-713
59	Novartis Investigative Site	Seoul		Korea, Republic of	150-950
60	Novartis Investigative Site	Bucharest	District 1	Romania	011422
61	Novartis Investigative Site	Bucharest	District 1	Romania	012064
62	Novartis Investigative Site	Bucharest	District 1	Romania
63	Novartis Investigative Site	Bucharest	District 2	Romania	021705
64	Novartis Investigative Site	Oradea	Jud. Bihor	Romania	410032
65	Novartis Investigative Site	Craiova	Jud. Dolj	Romania	200147
66	Novartis Investigative Site	Bucharest		Romania	060011
67	Novartis Investigative Site	Nitra	Slovak Republic	Slovakia	949 01
68	Novartis Investigative Site	Presov	Slovak Republic	Slovakia	08001
69	Novartis Investigative Site	Bratislava		Slovakia	831 06
70	Novartis Investigative Site	Liptovsky Mikulas		Slovakia	031 01
71	Novartis Investigative Site	Nitra		Slovakia	949 01
72	Novartis Investigative Site	Nitra		Slovakia	94901
73	Novartis Investigative Site	Nove Zamky		Slovakia	940 01
74	Novartis Investigative Site	Partizanske		Slovakia	958 01
75	Novartis Investigative Site	Presov		Slovakia	080 01
76	Novartis Investigative Site	Presov		Slovakia	081 01
77	Novartis Investigative Site	Ruzomberok		Slovakia	034 26
78	Novartis Investigative Site	Sala		Slovakia	927 03
79	Novartis Investigative Site	Sered		Slovakia	926 00
80	Novartis Investigative Site	Zvolen		Slovakia	960 01
81	Novartis Investigative Site	Granada	Andalucia	Spain	18012
82	Novartis Investigative Site	Sevilla	Andalucia	Spain	41009
83	Novartis Investigative Site	Badalona	Cataluña	Spain	08914
84	Novartis Investigative Site	Centelles	Cataluña	Spain	08540
85	Novartis Investigative Site	Tarragona	Cataluña	Spain	43350
86	Novartis Investigative Site	Alicante	Comunidad Valenciana	Spain	03004
87	Novartis Investigative Site	Alzira	Comunidad Valenciana	Spain	46600
88	Novartis Investigative Site	Santiago de Compostela	Galicia	Spain	15706
89	Novartis Investigative Site	Barcelona		Spain
90	Novartis Investigative Site	Madrid		Spain	28046

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01281306
• Other Study ID Numbers: CLCZ696A2223; 2010-022326-32
• First Posted: Jan 21, 2011
• Last Update Posted: Jan 29, 2016
• Last Verified: Dec 1, 2015

• Keywords provided by Novartis Pharmaceuticals: hypertension; blood pressure; LCZ696; dual-acting; neprilysin; nep inhibitor; vasopeptidase; angiotensin receptor; angiotensin receptor neprilysin inhibitor (ARNi)
• Additional relevant MeSH terms: Hypertension; Systolic Murmurs; Valsartan; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	This study consisted of a single-blind run-in period and a double-blind (DB) period. During the 3 to 4 week run-in, participants were assessed for randomization eligibility into the DB period. 910 participants randomized. 3 participants were mis-randomized and did not receive study treatment. Therefore, the participant flow shows 907 participants.
Pre-assignment Detail	In the double blind period, participants were randomized in a 2:2:2:2:2:2:1 ratio to AHU377 400 mg + valsartan 320 mg, AHU377 200 mg + valsartan 320 mg, AHU377 100 mg + valsartan 320 mg, AHU377 50 mg + valsartan 320 mg,valsartan 320 mg, LCZ696 400 mg and placebo, respectively.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Period Title: Overall Study
STARTED	144	145	141	134	143	142	58
Full Analysis Set	143	145	141	133	143	142	58
Safety Set	143	145	141	133	143	142	58
Ambulatory Blood Pressure Monitoring Set	95	99	92	95	93	91	35
COMPLETED	136	141	133	123	134	135	51
NOT COMPLETED	8	4	8	11	9	7	7

Baseline Characteristics

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo	Total
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.	Total of all reporting groups
Overall Participants	144	145	141	134	143	142	58	907
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.7 (11.36)	61.7 (11.44)	61.0 (11.03)	62.0 (10.73)	62.0 (11.45)	61.2 (10.60)	60.8 (11.81)	61.5 (11.13)
Sex: Female, Male (Count of Participants)
Female	78 54.2%	60 41.4%	53 37.6%	61 45.5%	60 42%	71 50%	29 50%	412 45.4%
Male	66 45.8%	85 58.6%	88 62.4%	73 54.5%	83 58%	71 50%	29 50%	495 54.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)
Description	Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Only participants of the full analysuis set (FAS), who had measurements at both baseline and week 8, were included in the analysis. The FAS included all randomized participants who received at least one dose of double-blind study medication.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	143	144	141	132	143	142	57
Least Squares Mean (Standard Error) [mmHg]	-20.89 (1.22)	-23.55 (1.21)	-21.26 (1.23)	-19.31 (1.27)	-16.13 (1.22)	-21.78 (1.22)	-6.99 (1.92)

2. Secondary Outcome

Title	Change From Baseline in Mean Diastolic Blood Pressure (msDBP)
Description	Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Only participants of the full analysuis set (FAS), who had measurements at both baseline and week 8, were included in the analysis. The FAS included all randomized participants who received at least one dose of double-blind study medication.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	143	144	141	132	143	142	57
Least Squares Mean (Standard Error) [mmHg]	-8.47 (0.76)	-9.76 (0.75)	-8.04 (0.76)	-7.15 (0.79)	-7.28 (0.76)	-9.61 (0.75)	-3.38 (1.19)

3. Secondary Outcome

Title	Change From Baseline in Mean 24 Hour Ambulatory SBP (maSBP) and Mean 24 Hour Ambulatory DBP (maDBP)
Description	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of randomized participants, who had ABPM measurements at both baseline and week 8, were included in the analysis.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	94	98	92	95	93	90	35
maSBP	-12.14 (0.71)	-15.66 (0.69)	-14.33 (0.72)	-11.36 (0.70)	-9.59 (0.71)	-12.98 (0.71)	-2.12 (1.15)
maDBP	-5.81 (0.44)	-7.03 (0.42)	-6.46 (0.44)	-5.36 (0.43)	-5.23 (0.44)	-6.20 (0.44)	-0.79 (0.71)

4. Secondary Outcome

Title	Change From Baseline in Daytime maSBP and maDBP
Description	Twenty four hour ABPM was performed twice during the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of randomized participants, who had ABPM measurements at both baseline and week 8, were included in the analysis.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	94	98	92	95	93	90	35
maSBP	-12.62 (1.21)	-15.85 (1.19)	-14.43 (1.23)	-11.50 (1.21)	-9.60 (1.22)	-13.32 (1.23)	-2.39 (1.98)
maDBP	-5.93 (0.77)	-7.13 (0.75)	-6.57 (0.78)	-5.39 (0.77)	-5.40 (0.77)	-6.16 (0.78)	-0.98 (1.26)

5. Secondary Outcome

Title	Change From Baseline in Nighttime maSBP and maDBP
Description	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of randomized participants, who had ABPM measurements at both baseline and week 8, were included in the analysis.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	91	98	90	95	92	90	35
maSBP	-11.57 (1.23)	-15.27 (1.19)	-14.74 (1.23)	-10.80 (1.21)	-8.88 (1.22)	-12.34 (1.23)	-1.36 (1.98)
maDBP	-5.27 (0.78)	-6.79 (0.75)	-6.45 (0.78)	-5.27 (0.77)	-4.49 (0.77)	-6.36 (0.78)	-0.22 (1.26)

6. Secondary Outcome

Title	Change From Baseline in Mean Sitting Pulse Pressure
Description	Pulse rate measurements were performed. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Only participants of the full analysis set (FAS), who had measurements at both baseline and week 8, were included in the analysis. The FAS included all randomized participants who received at least one dose of double-blind study medication.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	143	144	141	132	143	142	57
Least Squares Mean (Standard Error) [mmHg]	-12.39 (0.91)	-13.91 (0.90)	-13.18 (0.91)	-12.01 (0.95)	-8.80 (0.91)	-12.18 (0.91)	-3.74 (1.43)

7. Secondary Outcome

Title	Change From Baseline in Mean Ambulatory Pulse Pressure
Description	Pulse rate measurements were performed. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of randomized participants, who had ABPM measurements at both baseline and week 8, were included in the analysis.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	94	98	92	95	93	90	35
Least Squares Mean (Standard Error) [mmHg]	-6.23 (0.39)	-8.51 (0.38)	-7.71 (0.40)	-6.00 (0.39)	-4.40 (0.39)	-6.84 (0.39)	-1.09 (0.63)

8. Secondary Outcome

Title	Change From Baseline in maSBP and maDBP in Dippers
Description	Twenty four hour ABPM was performed twice during the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of randomized participants, who had ABPM measurements at both baseline and week 8, were included in the analysis.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	32	42	38	42	38	37	19
maSBP	-11.43 (1.12)	-15.59 (1.00)	-12.04 (1.05)	10.60 (1.01)	-9.85 (1.03)	-13.09 (1.05)	-2.39 (1.45)
maDBP	-4.62 (0.70)	-7.33 (0.62)	-5.49 (0.65)	-5.07 (0.63)	-5.53 (0.64)	-6.03 (0.65)	-0.98 (0.90)

9. Secondary Outcome

Title	Change From Baseline in maSBP and maDBP in Non-dippers
Description	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of randomized participants, who had ABPM measurements at both baseline and week 8, were included in the analysis.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	59	56	53	53	54	53	16
maSBP	-12.81 (0.91)	-16.08 (0.94)	-16.37 (0.97)	-12.17 (0.99)	-9.73 (0.96)	-13.12 (0.96)	-1.46 (1.75)
maDBP	-6.65 (0.56)	-6.91 (0.58)	-7.31 (0.60)	-5.79 (0.61)	-5.10 (0.59)	-6.34 (0.59)	-0.49 (1.08)

10. Secondary Outcome

Title	Change From Baseline in msSBP and msDBP in Participants < 65 Years of Age
Description	Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Only participants of the full analysuis set (FAS), who were < 65 years of age and had measurements at both baseline and week 8, were included in the analysis. The FAS included all randomized participants who received at least one dose of double-blind study medication.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	75	75	78	66	73	79	28
msSBP	-20.95 (1.68)	-24.45 (1.67)	-20.94 (1.63)	-18.09 (1.79)	-16.96 (1.71)	-21.06 (1.63)	-8.94 (2.73)
msDBP	-8.97 (1.11)	-10.94 (1.11)	-8.83 (1.09)	-8.07 (1.19)	-6.93 (1.13)	-10.25 (1.08)	-5.19 (1.82)

11. Secondary Outcome

Title	Change From Baseline in msSBP and msDBP in Participants >= 65 Years of Age
Description	Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Only participants of the full analysuis set (FAS), who were >= 65 years of age and had measurements at both baseline and week 8, were included in the analysis. The FAS included all randomized participants who received at least one dose of double-blind study medication.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	68	69	63	66	70	63	29
msSBP	-20.93 (1.79)	-22.66 (1.76)	-21.72 (1.85)	-20.64 (1.81)	-15.48 (1.75)	-22.83 (1.84)	-5.10 (2.71)
msDBP	-7.89 (1.02)	-8.44 (1.00)	-7.06 (1.05)	-6.17 (1.03)	-7.62 (0.99)	-8.89 (1.04)	-1.46 (1.54)

12. Secondary Outcome

Title	Change From Baseline in maSBP and maDBP in Participants < 65 Years of Age
Description	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of randomized participants, who were leass than 65 years of age and had ABPM measurements at both baseline and week 8, were included in the analysis.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	44	50	46	47	44	48	15
maSBP	-12.16 (0.98)	-15.06 (0.91)	-14.42 (0.95)	-10.39 (0.95)	-9.55 (0.99)	-13.98 (0.93)	-2.24 (1.67)
maDBP	-6.74 (0.67)	-7.81 (0.62)	-7.93 (0.65)	-5.69 (0.65)	-5.94 (0.67)	-7.32 (0.63)	-1.53 (1.14)

13. Secondary Outcome

Title	Change From Baseline in maSBP and maDBP in Participants >= 65 Years of Age
Description	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of randomized participants, who were >= 65 years of age and had ABPM measurements at both baseline and week 8, were included in the analysis.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	50	48	46	48	49	42	20
maSBP	-12.10 (1.04)	-16.08 (1.03)	-14.20 (1.08)	-12.25 (1.04)	-9.73 (1.02)	-11.88 (1.10)	-1.95 (1.59)
maDBP	-4.94 (0.58)	-6.00 (0.57)	-4.86 (0.60)	-4.93 (0.58)	-4.58 (0.56)	-5.04 (0.61)	-0.01 (0.88)

14. Secondary Outcome

Title	Number of Participants Who Achieved Blood Pressure Control and Blood Pressure Response
Description	Sitting BP measurements were performed at trough (23-26 hours post-morning dose). Blood pressure control was defined as msSBP/MSDBP < 140/90 mmHg. Blood pressure response in msSBP was defined as <140 mmHg or a reduction >= 20mmHg from baseline. Blood pressure response in msDBP was defined as < 90 mmHg or a reduction >= 10 mmHg from baseline.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Only participants of the full analysuis set (FAS), who had week 8 measurements, were included in the analysis. The FAS included all randomized participants who received at least one dose of double-blind study medication.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	143	144	141	132	143	142	57
Blood pressure control	72 50%	86 59.3%	71 50.4%	58 43.3%	57 39.9%	76 53.5%	8 13.8%
msSBP response	88 61.1%	101 69.7%	93 66%	81 60.4%	72 50.3%	94 66.2%	11 19%
msDBP response	112 77.8%	126 86.9%	114 80.9%	101 75.4%	111 77.6%	118 83.1%	39 67.2%

15. Secondary Outcome

Title	Number of Participants With Adverse Events, Serious Adverse Events and Death
Description	Adverse event monitoring was conducted throughout the study.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: The safety analysis set included all randomized participants who received at least one dose of study medication.

Arm/Group Title	VAL + AHU 400 mg	VAL + AHU 200 mg	VAL + AHU 100 mg	VAL + AHU 50 mg	VAL 320 mg	LCZ 400 mg	Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
Measure Participants	143	145	141	133	143	142	58
Adverse events (non-serious and serious)	40 27.8%	31 21.4%	29 20.6%	25 18.7%	38 26.6%	42 29.6%	20 34.5%
Serious adverse events	3 2.1%	1 0.7%	1 0.7%	0 0%	1 0.7%	1 0.7%	1 1.7%
Deaths	1 0.7%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	VAL + AHU 400 mg		VAL + AHU 200 mg		VAL + AHU 100 mg		VAL + AHU 50 mg		VAL 320 mg		LCZ 400 mg		Placebo
Arm/Group Description	Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.		Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.		Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.		Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.		Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.		Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.		Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.
All Cause Mortality
	VAL + AHU 400 mg		VAL + AHU 200 mg		VAL + AHU 100 mg		VAL + AHU 50 mg		VAL 320 mg		LCZ 400 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	VAL + AHU 400 mg		VAL + AHU 200 mg		VAL + AHU 100 mg		VAL + AHU 50 mg		VAL 320 mg		LCZ 400 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/143 (2.1%)		1/145 (0.7%)		1/141 (0.7%)		0/133 (0%)		1/143 (0.7%)		1/142 (0.7%)		1/58 (1.7%)
General disorders
Sudden death	1/143 (0.7%)		0/145 (0%)		0/141 (0%)		0/133 (0%)		0/143 (0%)		0/142 (0%)		0/58 (0%)
Hepatobiliary disorders
Cholelithiasis	1/143 (0.7%)		0/145 (0%)		0/141 (0%)		0/133 (0%)		0/143 (0%)		0/142 (0%)		0/58 (0%)
Infections and infestations
Postoperative wound infection	0/143 (0%)		0/145 (0%)		1/141 (0.7%)		0/133 (0%)		0/143 (0%)		0/142 (0%)		0/58 (0%)
Injury, poisoning and procedural complications
Thoracic vertebral fracture	0/143 (0%)		0/145 (0%)		0/141 (0%)		0/133 (0%)		1/143 (0.7%)		0/142 (0%)		0/58 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	0/143 (0%)		0/145 (0%)		0/141 (0%)		0/133 (0%)		0/143 (0%)		1/142 (0.7%)		0/58 (0%)
Psychiatric disorders
Schizophrenia	0/143 (0%)		1/145 (0.7%)		0/141 (0%)		0/133 (0%)		0/143 (0%)		0/142 (0%)		0/58 (0%)
Renal and urinary disorders
Calculus urinary	0/143 (0%)		0/145 (0%)		0/141 (0%)		0/133 (0%)		0/143 (0%)		0/142 (0%)		1/58 (1.7%)
Skin and subcutaneous tissue disorders
Angioedema	1/143 (0.7%)		0/145 (0%)		0/141 (0%)		0/133 (0%)		0/143 (0%)		0/142 (0%)		0/58 (0%)
Other (Not Including Serious) Adverse Events
	VAL + AHU 400 mg		VAL + AHU 200 mg		VAL + AHU 100 mg		VAL + AHU 50 mg		VAL 320 mg		LCZ 400 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/143 (0.7%)		2/145 (1.4%)		1/141 (0.7%)		2/133 (1.5%)		4/143 (2.8%)		1/142 (0.7%)		3/58 (5.2%)
Gastrointestinal disorders
Dyspepsia	1/143 (0.7%)		2/145 (1.4%)		1/141 (0.7%)		2/133 (1.5%)		4/143 (2.8%)		1/142 (0.7%)		3/58 (5.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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