Efficacy and Safety of LCZ696 Compared to Placebo in Patients With Essential Hypertension

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01193101
• Collaborator: (none)
• Enrollment: 389
• Locations: 34
• Arms: 4
• Duration (Months): 8
• Patients Per Site: 11.4
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This study is a phase 2 study in patients with essential hypertension.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 389 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-ranging Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Placebo After 8 Weeks Treatment in Patients With Essential Hypertension
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 100 mg LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	Drug: LCZ696; LCZ696; Drug: Placebo; matching placebo to LCZ696
Experimental: LCZ696 200 mg LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	Drug: LCZ696; LCZ696; Drug: Placebo; matching placebo to LCZ696
Experimental: LCZ696 400 mg LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Drug: LCZ696; LCZ696; Drug: Placebo; matching placebo to LCZ696
Placebo Comparator: Placebo Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.	Drug: Placebo; matching placebo to LCZ696

Outcome Measures

Primary Outcome Measures

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

   Sitting BP measurements were performed at screening through the end of the study at every study visit. A negative change from baseline indicates improvement.

Secondary Outcome Measures

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

   Sitting BP measurements were performed at screening through the end of the study at every study visit. A negative change from baseline indicates improvement.

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

   Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. A negative change from baseline indicates improvement.

3. Change From Baseline in Daytime Mean Ambulatory DBP and SBP [Baseline, 8 weeks]

   Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. Daytime mean SBP and DBP were the averages of the hourly means between 6 am and 10 pm. A negative change from baseline indicates improvement.

4. Change From Baseline in Nighttime Mean Ambulatory DBP and SBP [Baseline, 8 weeks]

   Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. Nighttime mean SBP and DBP were the averages of the hourly means between 10 pm and 6 am. A negative change from baseline indicates improvement.

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

   Mean sitting pulse pressure is the difference in msSBP and msDBP (msSBP - msDBP). A negative change from baseline indicates improvement.

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

   Mean ambulatory pulse pressure is the difference in maSBP and maDBP (maSBP - maDBP). A negative change from baseline indicates improvement.

7. Number of Participants Who Achieved a Successful Response in msDBP [8 weeks]

   Successful response in msDBP is defined as msDBP <90 mmHg or a reduction ≥ 10 mmHg from baseline.

8. Number of Participants Who Achieved a Successful Response in msSBP [8 weeks]

   Successful response in msSBP is defined as msSBP <140 mmHg or a reduction ≥ 20 mmHg from baseline.

9. Number of Participants Who Achieved Successful BP Control [8 weeks]

   BP control is defined as BP < 140/90 mmHg.

10. Trough to Post-dosing Hour Ratio for Change From Baseline in 24-hour Mean Ambulatory DBP [baseline, 8 weeks]

    Trough to post-dosing hour ratio at each post-dosing hour = [trough LSM of LCZ696 - trough LSM of placebo]/[post-dosing hour LSM of LCZ696 - post-dosing hour LSM of placebo]

11. Trough to Post-dosing Hour Ratio for Change From Baseline in 24-hour Mean Ambulatory SBP [baseline, 8 weeks]

    Trough to post-dosing hour ratio at each post-dosing hour = [trough LSM of LCZ696 - trough LSM of placebo]/[post-dosing hour LSM of LCZ696 - post-dosing hour LSM of placebo]

12. Change From Week 8 to Week 9 in msDBP and msSBP After Single-blind Placebo Withdrawal at Week 8 [8 weeks, 9 weeks]

    From week 8 to week 9, participants entered a single-blind placebo withdrawal period to assess the effect of LCZ696 on blood pressure following its discontinuation. Participants, who were randomized to the LCZ696 treatment groups, were discontinued from CLCZ696 at the end of week 8 and all 4 treatment groups received single-blind placebo for 1 week post week 8. A positive change from week 8 to week 9 indicates worsening.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Patients must give written informed consent before any assessment is performed.

2. Patients with mild to moderate essential hypertension, untreated or currently taking antihypertensive therapy (mean sitting diastolic blood pressure ≥ 95 mmHg and < 110 mmHg, and mean sitting systolic blood pressure ≥ 140 mmHg and < 180 mmHg).

3. Patients must be willing and able to undergo ambulatory blood pressure monitoring for a 24-hr period at the beginning and the end of the 8-week treatment.

4. Patient must be able to communicate and comply with all study requirements and demonstrate good medication compliance.

Exclusion Criteria:

1. Patients with severe hypertension.

2. Patients with history of angioedema, drug-related or otherwise

3. Pregnant or nursing women

4. Women of child-bearing potential , who do not use adequate birth control methods

5. History or evidence of a secondary form of hypertension.

6. History of angina pectoris, myocardial infarction, coronary bypass surgery, ischemic heart disease, surgical or percutaneous arterial intervention of any kind, stroke, TIA, carotid artery stenosis, aortic aneurysm, or peripheral arterial disease.

7. Diabetes mellitus.

8. Previous or current diagnosis of heart failure (NYHA Class II-IV).

9. Clinically significant valvular heart disease at the time of screening.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Shijiazhuang	Hebei	China	050000
2	Novartis Investigative Site	Tianjin	Tianjin	China	300142
3	Novartis Investigative Site	Hangzhou	Zhejiang	China	310009
4	Novartis Investigative Site	Beijing		China	100044
5	Novartis Investigative Site	Beijing		China	100730
6	Novartis Investigative Site	Chongqing		China	400042
7	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	231-0023
8	Novartis Investigative Site	Shimotsuke-city	Tochigi	Japan	329-0498
9	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-0031
10	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-8655
11	Novartis Investigative Site	Chiyoda-ku	Tokyo	Japan	100-0005
12	Novartis Investigative Site	Kiyose-city	Tokyo	Japan	204-0021
13	Novartis Investigative Site	Kunitachi	Tokyo	Japan	186-0001
14	Novartis Investigative Site	Minato-ku	Tokyo	Japan	105-7390
15	Novartis Investigative Site	Minato-ku	Tokyo	Japan	108-0075
16	Novartis Investigative Site	Ota-ku	Tokyo	Japan	143-0023
17	Novartis Investigative Site	Shinagawa-ku	Tokyo	Japan	141-0032
18	Novartis Investigative Site	Shinagawa-ku	Tokyo	Japan	142-0053
19	Novartis Investigative Site	Shinagawa-ku	Tokyo	Japan	142-0063
20	Novartis Investigative Site	Toshima-ku	Tokyo	Japan	171-0021
21	Novartis Investigative Site	Bucheon	Gyeonggi-do	Korea, Republic of	424-717
22	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	137-701
23	Novartis Investigative Site	Koyang	Kyunggi	Korea, Republic of	410-719
24	Novartis Investigative Site	Daegu		Korea, Republic of	705-703
25	Novartis Investigative Site	Seoul		Korea, Republic of	150-950
26	Novartis Investigative Site	Seoul		Korea, Republic of	152-703
27	Novartis Investigative Site	Changhua		Taiwan	500
28	Novartis Investigative Site	Taichung		Taiwan	40447
29	Novartis Investigative Site	Taipei		Taiwan	10002
30	Novartis Investigative Site	Taipei		Taiwan	10449
31	Novartis Investigative Site	Taipei		Taiwan	114
32	Novartis Investigative Site	Bangkok		Thailand	10400
33	Novartis Investigative Site	Bangkok		Thailand	10700
34	Novartis Investigative Site	Chiang Mai		Thailand	50200

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: NCT01193101
• Other Study ID Numbers: CLCZ696A2219
• First Posted: Sep 1, 2010
• Last Update Posted: Feb 15, 2016
• Last Verified: Jan 1, 2016

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

Study Results

Participant Flow

Recruitment Details	This study comprised 3 periods: a 4 week washout and placebo run-in period, an 8 week randomized, double-blind period and a 1 week single-blind, placebo withdrawal period.
Pre-assignment Detail	In the run-in period, 457 participants were enrolled. Of the 457 participants, 389 participants were eligible for randomization and randomized in a 1:1:1:1 ratio to each treatment group.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Period Title: Overall Study
STARTED	100	101	96	92
Full Analysis Set	100	101	96	92
Placebo Withdrawal Set	95	94	93	80
COMPLETED	95	94	93	80
NOT COMPLETED	5	7	3	12

Baseline Characteristics

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo	Total
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.	Total of all reporting groups
Overall Participants	100	101	96	92	389
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.5 (10.03)	52.1 (8.82)	50.9 (9.81)	50.9 (10.65)	51.6 (9.82)
Sex: Female, Male (Count of Participants)
Female	40 40%	27 26.7%	23 24%	24 26.1%	114 29.3%
Male	60 60%	74 73.3%	73 76%	68 73.9%	275 70.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP)
Description	Sitting BP measurements were performed at screening through the end of the study at every study visit. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and week 8 values, were analyzed. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	100	98	96	92
Least Squares Mean (Standard Error) [mmHg]	-11.53 (0.88)	-10.98 (0.89)	-12.45 (0.90)	-3.69 (0.92)

2. Secondary Outcome

Title	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)
Description	Sitting BP measurements were performed at screening through the end of the study at every study visit. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and week 8 values, were analyzed. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	100	98	96	92
Least Squares Mean (Standard Error) [mmHg]	-16.83 (1.25)	-17.54 (1.27)	-20.35 (1.28)	-4.97 (1.30)

3. Secondary Outcome

Title	Change From Baseline in 24 Hour Mean Ambulatory DBP and SBP
Description	Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and week 8 values, were analyzed. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	81	84	82	73
maDBP	-8.34 (0.50)	-9.33 (0.49)	-9.69 (0.50)	0.28 (0.52)
maSBP	-13.07 (0.65)	-15.18 (0.64)	-15.98 (0.65)	0.19 (0.68)

4. Secondary Outcome

Title	Change From Baseline in Daytime Mean Ambulatory DBP and SBP
Description	Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. Daytime mean SBP and DBP were the averages of the hourly means between 6 am and 10 pm. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and week 8 values, were analyzed. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	81	84	82	73
maDBP	-8.46 (0.81)	-8.65 (0.80)	-9.77 (0.81)	-0.13 (0.85)
maSBP	-13.29 (1.08)	-14.62 (1.06)	-16.58 (1.08)	0.01 (1.13)

5. Secondary Outcome

Title	Change From Baseline in Nighttime Mean Ambulatory DBP and SBP
Description	Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. Nighttime mean SBP and DBP were the averages of the hourly means between 10 pm and 6 am. A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and week 8 values, were analyzed. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	81	83	82	73
maDBP	-7.96 (0.81)	-10.36 (0.80)	-9.47 (0.81)	0.97 (0.85)
maSBP	-12.27 (1.08)	-16.14 (1.07)	-14.65 (1.08)	0.61 (1.13)

6. Secondary Outcome

Title	Change From Baseline in Mean Sitting Pulse Pressure
Description	Mean sitting pulse pressure is the difference in msSBP and msDBP (msSBP - msDBP). A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and week 8 values, were analyzed. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	100	98	96	92
Least Squares Mean (Standard Error) [mmHg]	-5.11 (0.81)	-6.49 (0.83)	-7.82 (0.83)	-1.09 (0.85)

7. Secondary Outcome

Title	Change From Baseline in Mean Ambulatory Pulse Pressure
Description	Mean ambulatory pulse pressure is the difference in maSBP and maDBP (maSBP - maDBP). A negative change from baseline indicates improvement.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and week 8 values, were analyzed. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	81	84	82	73
Least Squares Mean (Standard Error) [mmHg]	-4.68 (0.30)	-5.84 (0.29)	-6.31 (0.30)	-0.08 (0.31)

8. Secondary Outcome

Title	Number of Participants Who Achieved a Successful Response in msDBP
Description	Successful response in msDBP is defined as msDBP <90 mmHg or a reduction ≥ 10 mmHg from baseline.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had week 8 values, were analyzed. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	100	98	96	92
Number [Participants]	65 65%	64 63.4%	67 69.8%	24 26.1%

9. Secondary Outcome

Title	Number of Participants Who Achieved a Successful Response in msSBP
Description	Successful response in msSBP is defined as msSBP <140 mmHg or a reduction ≥ 20 mmHg from baseline.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had week 8 values, were analyzed. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	100	98	96	92
Number [Participants]	59 59%	62 61.4%	66 68.8%	27 29.3%

10. Secondary Outcome

Title	Number of Participants Who Achieved Successful BP Control
Description	BP control is defined as BP < 140/90 mmHg.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had week 8 values, were analyzed. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	100	98	96	92
Number [Participants]	47 47%	48 47.5%	52 54.2%	14 15.2%

11. Secondary Outcome

Title	Trough to Post-dosing Hour Ratio for Change From Baseline in 24-hour Mean Ambulatory DBP
Description	Trough to post-dosing hour ratio at each post-dosing hour = [trough LSM of LCZ696 - trough LSM of placebo]/[post-dosing hour LSM of LCZ696 - post-dosing hour LSM of placebo]
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.
Measure Participants	100	98	96
Hour 1	0.95	1.32	1.28
Hour 2	0.76	1.03	0.90
Hour 3	0.64	1.35	0.91
Hour 4	0.77	1.30	1.18
Hour 5	0.82	1.18	1.05
Hour 6	0.73	1.04	1.21
Hour 7	0.68	1.00	1.03
Hour 8	0.75	0.88	0.99
Hour 9	0.80	1.07	1.01
Hour 10	0.76	1.15	1.11
Hour 11	0.82	1.31	1.19
Hour 12	0.56	0.92	0.89
Hour 13	0.67	0.86	0.88
Hour 14	0.69	0.91	0.85
Hour 15	0.57	0.69	0.74
Hour 16	0.58	0.65	0.80
Hour 17	0.89	0.92	1.02
Hour 18	0.86	0.92	1.07
Hour 19	0.83	0.99	1.13
Hour 20	0.84	1.06	1.18
Hour 21	0.76	1.02	1.02
Hour 22	0.98	1.09	0.80
Hour 23	1.02	0.93	0.81
Hour 24	1.00	1.00	1.00

12. Secondary Outcome

Title	Trough to Post-dosing Hour Ratio for Change From Baseline in 24-hour Mean Ambulatory SBP
Description	Trough to post-dosing hour ratio at each post-dosing hour = [trough LSM of LCZ696 - trough LSM of placebo]/[post-dosing hour LSM of LCZ696 - post-dosing hour LSM of placebo]
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.
Measure Participants	100	98	96
Hour 1	0.98	1.29	1.16
Hour 2	1.01	1.26	1.28
Hour 3	0.97	1.35	1.13
Hour 4	0.89	1.21	1.24
Hour 5	0.93	1.20	1.07
Hour 6	0.87	1.20	1.33
Hour 7	0.69	0.89	0.97
Hour 8	0.74	0.86	1.08
Hour 9	0.74	0.90	0.99
Hour 10	0.84	1.17	1.14
Hour 11	0.80	1.15	1.15
Hour 12	0.69	1.01	1.08
Hour 13	0.87	0.92	1.21
Hour 14	0.77	0.90	1.02
Hour 15	0.67	0.79	1.01
Hour 16	0.84	0.80	1.14
Hour 17	1.12	1.06	1.26
Hour 18	1.04	1.05	1.46
Hour 19	1.14	1.16	1.41
Hour 20	1.07	1.17	1.33
Hour 21	1.06	1.12	1.39
Hour 22	1.21	1.44	1.13
Hour 23	1.00	1.06	1.01
Hour 24	1.00	1.00	1.00

13. Secondary Outcome

Title	Change From Week 8 to Week 9 in msDBP and msSBP After Single-blind Placebo Withdrawal at Week 8
Description	From week 8 to week 9, participants entered a single-blind placebo withdrawal period to assess the effect of LCZ696 on blood pressure following its discontinuation. Participants, who were randomized to the LCZ696 treatment groups, were discontinued from CLCZ696 at the end of week 8 and all 4 treatment groups received single-blind placebo for 1 week post week 8. A positive change from week 8 to week 9 indicates worsening.
Time Frame	8 weeks, 9 weeks

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis, who had values at both week 8 and week 9, were included in the analysis. The FAS included all randomized participants.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Measure Participants	95	94	93	80
msDBP	4.8 (7.61)	5.1 (7.03)	5.6 (7.01)	-0.6 (6.34)
msSBP	8.0 (11.88)	8.8 (11.62)	11.6 (10.96)	-0.7 (10.50)

Adverse Events

Arm/Group Title	LCZ696 100 mg		LCZ696 200 mg		LCZ696 400 mg		Placebo
Arm/Group Description	LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.		LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.		LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.		Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
All Cause Mortality
	LCZ696 100 mg		LCZ696 200 mg		LCZ696 400 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	LCZ696 100 mg		LCZ696 200 mg		LCZ696 400 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/100 (0%)		1/101 (1%)		2/96 (2.1%)		0/92 (0%)
General disorders
Pyrexia	0/100 (0%)		0/101 (0%)		1/96 (1%)		0/92 (0%)
Hepatobiliary disorders
Hepatic function abnormal	0/100 (0%)		0/101 (0%)		1/96 (1%)		0/92 (0%)
Infections and infestations
Appendicitis	0/100 (0%)		1/101 (1%)		0/96 (0%)		0/92 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/100 (0%)		0/101 (0%)		1/96 (1%)		0/92 (0%)
Nervous system disorders
Dysarthria	0/100 (0%)		0/101 (0%)		1/96 (1%)		0/92 (0%)
Other (Not Including Serious) Adverse Events
	LCZ696 100 mg		LCZ696 200 mg		LCZ696 400 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/100 (16%)		11/101 (10.9%)		14/96 (14.6%)		15/92 (16.3%)
Infections and infestations
Nasopharyngitis	6/100 (6%)		6/101 (5.9%)		7/96 (7.3%)		7/92 (7.6%)
Upper respiratory tract infection	9/100 (9%)		3/101 (3%)		4/96 (4.2%)		4/92 (4.3%)
Nervous system disorders
Dizziness	1/100 (1%)		2/101 (2%)		3/96 (3.1%)		5/92 (5.4%)

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.