Study of the Safety and Efficacy of LCZ696 on Arterial Stiffness in Elderly Patients With Hypertension

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01692301
• Collaborator: (none)
• Enrollment: 454
• Locations: 47
• Arms: 2
• Duration (Months): 28
• Patients Per Site: 9.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The study examined the efficacy of LCZ696 in comparison to the ARB olmesartan on Central Aortic Systolic Blood Pressure (CASP) and other measures of central hemodynamics and arterial stiffness in elderly patients with an elevated systolic blood pressure (SBP) and widened pulse pressure (PP).

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: LCZ696; Drug: Olmesartan; Drug: LCZ696 matching placebo; Drug: Olmesartan matching placebo; Drug: amlodipine; Drug: hydrochlorothiazide	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 454 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind 52-week Study to Evaluate the Safety and Efficacy of an LCZ696 Regimen Compared to an Olmesartan Regimen on Arterial Stiffness Through Assessment of Central Blood Pressure in Elderly Patients With Hypertension
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 (sacubitril/valsartan) Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Drug: LCZ696; 200 mg tablet; Other Names: sacubitril/valsartan ; Drug: LCZ696 matching placebo; LCZ696 Matching Placebo tablet; Drug: Olmesartan matching placebo; Olmesartan matching placebo capsule; Drug: amlodipine; amlodipine 2.5 mg or 5 mg tablets; Drug: hydrochlorothiazide; hydrochlorothiazide 6.25mg, 12.5mg, or 25 mg tablets
Active Comparator: Olmesartan Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.	Drug: Olmesartan; 20 mg and 40 mg capsules; Drug: LCZ696 matching placebo; LCZ696 Matching Placebo tablet; Drug: amlodipine; amlodipine 2.5 mg or 5 mg tablets; Drug: hydrochlorothiazide; hydrochlorothiazide 6.25mg, 12.5mg, or 25 mg tablets

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 12 Weeks [baseline, 12 weeks]

   Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software. At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.

Secondary Outcome Measures

1. Change From Baseline in Mean Central Pulse (CPP) Pressure [Baseline, 12 weeks, and 52 weeks]

2. Change From Baseline in Mean Pulse Wave Velocity (PWV) [baseline, 12 weeks, and 52 weeks]

   Pulse wave velocity recordings were performed on patient while in a supine, face-up position. Tonometry was performed on the carotid simultaneously with the cuff inflation over the femoral artery. Two pulse wave velocity measures, meeting all quality control criteria were captured at baseline, week 12 and week 52.

3. Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 52 Weeks [baseline, 52 weeks]

   Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software. At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.

4. Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) [baseline, 12 weeks, and 52 weeks]

   At the first study visit, the patient had his/her blood pressure (BP) measured in both arms; the arm in which the highest sitting SBP was found was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for 5 minutes, SBP were measured 3 times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1- to 2-minute intervals and the mean of those 3 measurements was used as the average sitting office BP for that visit.

5. Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) [baseline, 12 weeks, and 52 weeks]

   At the first study visit, the patient had his/her blood pressure (BP) measured in both arms; the arm in which the highest sitting SBP was found was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for 5 minutes, DBP were measured 3 times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1- to 2-minute intervals and the mean of those 3 measurements was used as the average sitting office BP for that visit.

6. Change From Baseline in Mean Sitting Pulse Pressure (msPP) [baseline, 12 weeks, and 52 weeks]

   Mean sitting pulse pressure for each patient and visit was calculated as the difference between the calculated values of mean sitting systolic blood pressure and mean sitting diastolic blood pressure.

7. Change From Baseline in Mean Arterial Pressure (MAP) [baseline, 12 weeks, and 52 weeks]

   Mean arterial pressure (MAP) was calculated from mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) as (2 * msDBP + msSBP)/3.

8. Change From Baseline in Mean 24-hour Systolic Blood Pressure (maSBP) [Baseline, 12 weeks, and 52 weeks]

   An Ambulatory Blood Pressure Monitor (ABPM) measured a participant's blood pressure over a 24 hour period using an automated validated monitoring device at baseline, week 12 and at week 52 starting one day before each visit. The 24 hour maSBP was calculated by taking the mean of all ambulatory systolic blood pressure readings for the 24 hour period.

9. Change From Baseline in Mean 24-hour Diastolic Blood Pressure (maDBP) [Baseline, 12 weeks, and 52 weeks]

   An Ambulatory Blood Pressure Monitor (ABPM) measured a participant's blood pressure over a 24 hour period using an automated validated monitoring device at baseline, week 12 and at week 52 starting one day before each visit. The 24 hour maDBP was calculated by taking the mean of all ambulatory systolic blood pressure readings for the 24 hour period.

10. Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (maPP) [Baseline, 12 weeks, and 52 weeks]

    Mean 24 hour ambulatory pulse pressure was calculated as the difference between the mean 24 hour systolic and diastolic ambulatory blood pressure in corresponding visits i.e. baseline, week 12 and week 52.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Male and female patients ≥ 60 years of age.

2. Patients with essential hypertension, untreated or currently taking antihypertensive therapy.

3. Untreated patients must have an office msSBP ≥150 mmHg and <180 mmHg at Visit 101 and Visit 201 if they are newly diagnosed or have not been treated with antihypertensive drugs for the 4 weeks prior to Visit 1.

4. Treated patients must have an office msSBP ≥140 mmHg and <180 mmHg at Visit 102 (or Visit 103) and msSBP ≥150 mmHg and <180 mmHg at Visit 201 if they have been treated with antihypertensive drugs for the 4 weeks prior to Visit 1.

5. All patients must have pulse pressure >60 mmHg at Visit 201. Pulse pressure is defined as msSBP- msDBP.

6. Patients must have a difference in msSBP within +/-15 mmHg between Visit 201 (randomization) and the visit immediately prior to Visit 201.

Key Exclusion Criteria:

1. Malignant or severe hypertension (grade 3 of WHO classification; msDBP ≥110 mmHg and/or msSBP ≥ 180 mmHg)

2. History of angioedema, drug-related or otherwise.

3. History or evidence of a secondary form of hypertension, including but not limited to any of the following: renal parenchymal hypertension, renovascular hypertension (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing's disease, pheochromocytoma, polycystic kidney disease, and drug-induced hypertension.

4. Transient ischemic cerebral attack (TIA) during the 12 months prior to Visit 1 or any history of stroke.

5. History of myocardial infarction, coronary bypass surgery or any percutaneous coronary intervention (PCI) during the 12 months prior to Visit 1.

6. History of atrial fibrillation or atrial flutter during the 3 months prior to Visit 1, or active atrial fibrillation or atrial flutter on the ECG at screening.

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	Baltimore	Maryland	United States	21204
4	Novartis Investigative Site	Belzoni	Mississippi	United States	39038
5	Novartis Investigative Site	Jackson	Mississippi	United States	39209
6	Novartis Investigative Site	St. Louis	Missouri	United States	63141
7	Novartis Investigative Site	Buffalo	New York	United States	14215
8	Novartis Investigative Site	Cincinnati	Ohio	United States	45224
9	Novartis Investigative Site	Houston	Texas	United States	77081
10	Novartis Investigative Site	Lake Jackson	Texas	United States	77566
11	Novartis Investigative Site	Pasadena	Texas	United States	77504
12	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1440AAD
13	Novartis Investigative Site	Ramos Mejia	Buenos Aires	Argentina	B1704ETD
14	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000CXH
15	Novartis Investigative Site	Barranquilla	Atlantico	Colombia
16	Novartis Investigative Site	Barranquilla		Colombia
17	Novartis Investigative Site	Paris		France	75015
18	Novartis Investigative Site	Berlin		Germany	10117
19	Novartis Investigative Site	Nuernberg		Germany	90471
20	Novartis Investigative Site	Athens		Greece	11525
21	Novartis Investigative Site	Athens		Greece	11526
22	Novartis Investigative Site	Thessaloniki		Greece	54642
23	Novartis Investigative Site	Treviglio	BG	Italy	24047
24	Novartis Investigative Site	Pisa	PI	Italy	56126
25	Novartis Investigative Site	San Daniele Del Friuli	UD	Italy	33038
26	Novartis Investigative Site	Shimotsuke-city	Tochigi	Japan	329-0498
27	Novartis Investigative Site	Bucheon	Gyeonggi-do	Korea, Republic of	424-717
28	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	110 744
29	Novartis Investigative Site	Moscow		Russian Federation	101990
30	Novartis Investigative Site	Moscow		Russian Federation	117198
31	Novartis Investigative Site	Moscow		Russian Federation	119992
32	Novartis Investigative Site	Saint Petersburg		Russian Federation	197022
33	Novartis Investigative Site	Saint-Petersburg		Russian Federation	197341
34	Novartis Investigative Site	Yaroslavl		Russian Federation	150047
35	Novartis Investigative Site	Sevilla	Andalucia	Spain	41071
36	Novartis Investigative Site	Jerez de La Frontera	Cadiz	Spain	11407
37	Novartis Investigative Site	Barcelona	Cataluna	Spain	08003
38	Novartis Investigative Site	Barcelona	Catalunya	Spain	08025
39	Novartis Investigative Site	Terrassa	Catalunya	Spain	08221
40	Novartis Investigative Site	Centelles	Cataluña	Spain	08540
41	Novartis Investigative Site	Puerto de Sagunto	Comunidad Valenciana	Spain	46520
42	Novartis Investigative Site	La Coruna	Galicia	Spain	15706
43	Novartis Investigative Site	Madrid		Spain	28034
44	Novartis Investigative Site	Madrid		Spain	28041
45	Novartis Investigative Site	Taipei	Taiwan, ROC	Taiwan	112
46	Novartis Investigative Site	Taichung		Taiwan	40447
47	Novartis Investigative Site	Taipei		Taiwan	114

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: NCT01692301
• Other Study ID Numbers: CLCZ696A2216; 2012-002899-14
• First Posted: Sep 25, 2012
• Last Update Posted: May 4, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Novartis Pharmaceuticals: hypertension, elderly, central aortic pulse pressure, central pulse pressure, pulse wave velocity
• Additional relevant MeSH terms: Hypertension; Amlodipine; Valsartan; Hydrochlorothiazide; Olmesartan; Olmesartan Medoxomil; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Period Title: Overall Study
STARTED	229	225
COMPLETED	184	183
NOT COMPLETED	45	42

Baseline Characteristics

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan	Total
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.	Total of all reporting groups
Overall Participants	229	225	454
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	68.2 (5.73)	67.2 (5.97)	67.7 (5.87)
Sex: Female, Male (Count of Participants)
Female	110 48%	107 47.6%	217 47.8%
Male	119 52%	118 52.4%	237 52.2%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 12 Weeks
Description	Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software. At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.
Time Frame	baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoint (week 12).

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	207	206
Least Squares Mean (Standard Error) [mmHg]	-12.57 (1.01)	-8.90 (1.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Sacubitril/Valsartan), Olmesartan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.66
	Confidence Interval	(2-Sided) 95%; -6.45 to -0.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.42
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Mean Central Pulse (CPP) Pressure
Time Frame	Baseline, 12 weeks, and 52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoint (week 12, week 52). Four patients did not have a successful CASP assessment at Week 12 but passed quality check at Week 52, thus 4 more patients were included in the Week 52 Endpoint analysis

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	229	225
Baseline to Week 12 (n = 207, 206)	-6.41 (0.69)	-3.96 (0.69)
Baseline to Week 52 (n = 209, 208)	-7.16 (0.69)	-6.65 (0.69)

3. Secondary Outcome

Title	Change From Baseline in Mean Pulse Wave Velocity (PWV)
Description	Pulse wave velocity recordings were performed on patient while in a supine, face-up position. Tonometry was performed on the carotid simultaneously with the cuff inflation over the femoral artery. Two pulse wave velocity measures, meeting all quality control criteria were captured at baseline, week 12 and week 52.
Time Frame	baseline, 12 weeks, and 52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoint (week 12 , week 52).

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	229	225
Baseline to week 12 (n= 192, 196)	-0.68 (0.12)	-0.57 (0.12)
Baseline to week 52 ( n= 199, 199)	-0.83 (0.13)	0.77 (0.13)

4. Secondary Outcome

Title	Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 52 Weeks
Description	Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software. At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.
Time Frame	baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoint (week 52). Four patients did not have a successful CASP assessment at Week 12 but passed quality check at Week 52, thus 4 more patients were included in the Week 52 Endpoint analysis.

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	209	208
Least Squares Mean (Standard Error) [mmHg]	-16.18 (0.96)	-14.70 (0.96)

5. Secondary Outcome

Title	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)
Description	At the first study visit, the patient had his/her blood pressure (BP) measured in both arms; the arm in which the highest sitting SBP was found was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for 5 minutes, SBP were measured 3 times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1- to 2-minute intervals and the mean of those 3 measurements was used as the average sitting office BP for that visit.
Time Frame	baseline, 12 weeks, and 52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoints (week 12, week 52).

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	229	225
Baseline to week 12 (n=226, 222)	-20.84 (1.06)	-14.57 (1.07)
Baseline to week 52 (n=226,223)	-23.91 (0.98)	-21.45 (0.99)

6. Secondary Outcome

Title	Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP)
Description	At the first study visit, the patient had his/her blood pressure (BP) measured in both arms; the arm in which the highest sitting SBP was found was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for 5 minutes, DBP were measured 3 times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1- to 2-minute intervals and the mean of those 3 measurements was used as the average sitting office BP for that visit.
Time Frame	baseline, 12 weeks, and 52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoints (week 12, week 52).

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	229	225
Baseline to week 12 (n=226, 222)	-7.86 (0.58)	-5.58 (0.59)
Baseline to week 52 (n=226,223)	-8.92 (0.57)	-7.85 (0.57)

7. Secondary Outcome

Title	Change From Baseline in Mean Sitting Pulse Pressure (msPP)
Description	Mean sitting pulse pressure for each patient and visit was calculated as the difference between the calculated values of mean sitting systolic blood pressure and mean sitting diastolic blood pressure.
Time Frame	baseline, 12 weeks, and 52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoints (week 12, week 52).

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	229	225
Baseline to week 12 (n=226,222)	-13.13 (0.82)	-8.86 (0.82)
Baseline to week 52 (n= 226, 223)	-15.02 (0.79)	-13.58 (0.80)

8. Secondary Outcome

Title	Change From Baseline in Mean Arterial Pressure (MAP)
Description	Mean arterial pressure (MAP) was calculated from mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) as (2 * msDBP + msSBP)/3.
Time Frame	baseline, 12 weeks, and 52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoints (week 12, week 52).

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	229	225
Baseline to week 12 (n=226, 222)	-12.19 (0.68)	-8.57 (0.68)
Baseline to week 52 (n=226, 223)	-13.92 (0.63)	-12.38 (0.64)

9. Secondary Outcome

Title	Change From Baseline in Mean 24-hour Systolic Blood Pressure (maSBP)
Description	An Ambulatory Blood Pressure Monitor (ABPM) measured a participant's blood pressure over a 24 hour period using an automated validated monitoring device at baseline, week 12 and at week 52 starting one day before each visit. The 24 hour maSBP was calculated by taking the mean of all ambulatory systolic blood pressure readings for the 24 hour period.
Time Frame	Baseline, 12 weeks, and 52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoints (week 12, week 52).

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	229	225
Baseline to week 12 (n= 164, 162)	-13.25 (0.62)	-9.14 (0.62)
Baseline to week 52 (n= 174, 176)	-14.15 (0.59)	-14.32 (0.58)

10. Secondary Outcome

Title	Change From Baseline in Mean 24-hour Diastolic Blood Pressure (maDBP)
Description	An Ambulatory Blood Pressure Monitor (ABPM) measured a participant's blood pressure over a 24 hour period using an automated validated monitoring device at baseline, week 12 and at week 52 starting one day before each visit. The 24 hour maDBP was calculated by taking the mean of all ambulatory systolic blood pressure readings for the 24 hour period.
Time Frame	Baseline, 12 weeks, and 52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoints (week 12, week 52).

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	229	225
Baseline to week 12 (n= 164, 162)	-7.44 (0.37)	-5.48 (0.36)
Baseline to week 52 (n= 174, 176)	-8.85 (0.35)	-8.44 (0.34)

11. Secondary Outcome

Title	Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (maPP)
Description	Mean 24 hour ambulatory pulse pressure was calculated as the difference between the mean 24 hour systolic and diastolic ambulatory blood pressure in corresponding visits i.e. baseline, week 12 and week 52.
Time Frame	Baseline, 12 weeks, and 52 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): All patients who were randomized. This endpoint included number of patients who had values at both baseline and endpoints (week 12, week 52).

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)	Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
Measure Participants	229	225
Baseline to Week 12 (n=164, 162 )	-5.77 (0.35)	-3.69 (0.35)
Baseline to week 52 (n=174, 176)	-5.26 (0.36)	-5.91 (0.35)

Adverse Events

Arm/Group Title	LCZ696 (Sacubitril/Valsartan)		Olmesartan
Arm/Group Description	Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.		Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
All Cause Mortality
	LCZ696 (Sacubitril/Valsartan)		Olmesartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LCZ696 (Sacubitril/Valsartan)		Olmesartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/229 (7%)		13/225 (5.8%)
Blood and lymphatic system disorders
ANAEMIA	1/229 (0.4%)		0/225 (0%)
COAGULOPATHY	1/229 (0.4%)		0/225 (0%)
IRON DEFICIENCY ANAEMIA	1/229 (0.4%)		0/225 (0%)
Cardiac disorders
ACUTE CORONARY SYNDROME	0/229 (0%)		1/225 (0.4%)
ACUTE MYOCARDIAL INFARCTION	0/229 (0%)		1/225 (0.4%)
ANGINA PECTORIS	0/229 (0%)		1/225 (0.4%)
ANGINA UNSTABLE	0/229 (0%)		1/225 (0.4%)
ATRIAL FIBRILLATION	2/229 (0.9%)		1/225 (0.4%)
CARDIO-RESPIRATORY ARREST	0/229 (0%)		1/225 (0.4%)
MYOCARDIAL INFARCTION	1/229 (0.4%)		0/225 (0%)
SUPRAVENTRICULAR TACHYCARDIA	1/229 (0.4%)		0/225 (0%)
Eye disorders
CATARACT	1/229 (0.4%)		0/225 (0%)
Gastrointestinal disorders
INGUINAL HERNIA	1/229 (0.4%)		0/225 (0%)
Hepatobiliary disorders
CHOLECYSTITIS CHRONIC	1/229 (0.4%)		0/225 (0%)
CHOLELITHIASIS	1/229 (0.4%)		0/225 (0%)
Infections and infestations
APPENDICITIS	1/229 (0.4%)		0/225 (0%)
DOUGLAS' ABSCESS	1/229 (0.4%)		0/225 (0%)
PERITONITIS	1/229 (0.4%)		0/225 (0%)
Injury, poisoning and procedural complications
HIP FRACTURE	0/229 (0%)		1/225 (0.4%)
PULMONARY CONTUSION	0/229 (0%)		1/225 (0.4%)
RIB FRACTURE	0/229 (0%)		2/225 (0.9%)
ROAD TRAFFIC ACCIDENT	1/229 (0.4%)		0/225 (0%)
SPINAL FRACTURE	0/229 (0%)		1/225 (0.4%)
SUBDURAL HAEMORRHAGE	0/229 (0%)		1/225 (0.4%)
TENDON RUPTURE	0/229 (0%)		1/225 (0.4%)
UPPER LIMB FRACTURE	1/229 (0.4%)		0/225 (0%)
VASCULAR GRAFT OCCLUSION	1/229 (0.4%)		0/225 (0%)
Investigations
BLOOD PRESSURE INCREASED	1/229 (0.4%)		0/225 (0%)
Musculoskeletal and connective tissue disorders
OSTEOCHONDROSIS	1/229 (0.4%)		0/225 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
SQUAMOUS CELL CARCINOMA	1/229 (0.4%)		0/225 (0%)
Nervous system disorders
BRAIN STEM INFARCTION	0/229 (0%)		1/225 (0.4%)
ISCHAEMIC STROKE	1/229 (0.4%)		0/225 (0%)
Respiratory, thoracic and mediastinal disorders
ATELECTASIS	1/229 (0.4%)		0/225 (0%)
PNEUMOTHORAX	0/229 (0%)		1/225 (0.4%)
PULMONARY EMBOLISM	1/229 (0.4%)		0/225 (0%)
PULMONARY PNEUMATOCELE	0/229 (0%)		1/225 (0.4%)
RESPIRATORY FAILURE	0/229 (0%)		1/225 (0.4%)
Vascular disorders
HYPERTENSIVE CRISIS	0/229 (0%)		1/225 (0.4%)
ORTHOSTATIC HYPOTENSION	1/229 (0.4%)		0/225 (0%)
Other (Not Including Serious) Adverse Events
	LCZ696 (Sacubitril/Valsartan)		Olmesartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/229 (31.9%)		55/225 (24.4%)
Gastrointestinal disorders
ABDOMINAL PAIN	5/229 (2.2%)		1/225 (0.4%)
DIARRHOEA	6/229 (2.6%)		5/225 (2.2%)
NAUSEA	5/229 (2.2%)		2/225 (0.9%)
General disorders
OEDEMA PERIPHERAL	6/229 (2.6%)		2/225 (0.9%)
Infections and infestations
INFLUENZA	7/229 (3.1%)		5/225 (2.2%)
NASOPHARYNGITIS	16/229 (7%)		12/225 (5.3%)
UPPER RESPIRATORY TRACT INFECTION	6/229 (2.6%)		6/225 (2.7%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	5/229 (2.2%)		7/225 (3.1%)
BACK PAIN	3/229 (1.3%)		10/225 (4.4%)
Nervous system disorders
DIZZINESS	12/229 (5.2%)		12/225 (5.3%)
HEADACHE	14/229 (6.1%)		10/225 (4.4%)
Respiratory, thoracic and mediastinal disorders
COUGH	10/229 (4.4%)		2/225 (0.9%)
Vascular disorders
HYPOTENSION	2/229 (0.9%)		5/225 (2.2%)

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.