A Study to Evaluate the Effect of LCZ696 on Aortic Stiffness in Subjects With Hypertension

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01870739
• Collaborator: (none)
• Enrollment: 115
• Locations: 4
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 28.8
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This was the first evaluation of the effects of LCZ696 on local and regional measures of aortic stiffness in subjects with mild to moderate hypertension and widened pulse pressure. The results of this exploratory study will help to understand the mechanism of action of LCZ696 and used to inform the design of future clinical studies with LCZ696 in subjects with cardiovascular diseases.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: sacubitril/valsartan (LCZ696); Drug: olmesartan; Other: placebo to sacubitril/valsartan (LCZ696); Other: placebo to olmesartan; Drug: Amlodipine (Optional)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 115 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Active-controlled, Parallel Group, 52-week Study to Evaluate the Effect of LCZ696 Compared to Olmesartan on Regional Aortic Stiffness in Subjects With Essential Hypertension
• Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: sacubitril/valsartan (LCZ696) Single drug treatment period: Patients received LCZ696 200mg once daily (q.d.) + placebo to 20 mg olmesartan q.d for 2 weeks. After 2 weeks, patients were dosed at the maintenance dose level (400 mg qd LCZ696 + placebo to 40 mg qd olmesartan) for 10 weeks. Add-on Period: After 12 weeks on single-drug treatment, patients continued in the study on the blinded maintenance dose and if required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to the treatment regimen and titrated according to the investigator's discretion to achieve target blood pressure.	Drug: sacubitril/valsartan (LCZ696); 200 mg tablets; Other: placebo to olmesartan; placebo; Drug: Amlodipine (Optional); If required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to treatment regimen
Active Comparator: olmesartan Single drug treatment period: Patients received 20 mg olmesartan q.d + placebo to LCZ696 200mg once daily (q.d.) for 2 weeks. After 2 weeks, patients were dosed at the maintenance dose level (40 mg olmesartan q.d + placebo to 400 mg qd LCZ696) for 10 weeks. Add-on Period: After 12 weeks on single-drug treatment, patients continued in the study on the blinded maintenance dose and if required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to the treatment regimen and titrated according to the investigator's discretion to achieve target blood pressure.	Drug: olmesartan; Other: placebo to sacubitril/valsartan (LCZ696); placebo; Drug: Amlodipine (Optional); If required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to treatment regimen

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Ascending Aorta Distensibility at 52 Week [Baseline, 52 weeks]

   Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Ascending aorta distensibility was one of the 3 components for measuring local arota distensibility.

2. Change From Baseline in Proximal Descending Aorta Distensibility at 52 Weeks [Baseline, 52 weeks]

   Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Proximal descending aorta distensibility was one of the 3 components for measuring local arota distensibility.

3. Change From Baseline in Distal Descending Aorta Distensibility at 52 Weeks [Baseline, 52 weeks]

   Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Distal descending aorta distensibility was one of the 3 components for measuring local arota distensibility.

Secondary Outcome Measures

1. Change From Baseline in Local Aortic Strain at 52 Weeks [Baseline, 52 weeks]

   Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic strain. Local aortic strain was measured by assessing ascending aorta strain, proximal descending aorta strain and distal descending aorta strain.

2. Change From Baseline in Regional Aortic Pulse Wave Velocity at 52 Weeks [Baseline, 52 weeks]

   Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of regional aortic pulse wave velocity.

3. Change From Baseline in Central Blood Pressure at 52 Weeks [Baseline, 52 weeks]

   Central blood pressure was determined by measuring central systolic blood pressure , diastolic blood pressure and pulse pressure.

4. Change From Baseline in Augmentation Pressure at 52 Weeks [Baseline, 52 weeks]

   Augmentation pressure is the added pressure during systole due to wave reflection.

5. Change From Baseline in Augmentation Index at 52 Weeks [Baseline, 52 weeks]

   Augmentation index (Alx) is the percentage of the central pulse pressure due to wave reflection.

6. Change From Baseline in Carotid-femoral Pulse Wave Velocity at 52 Weeks [Baseline, 52 weeks]

   For pulse wave velocity calculation, the pressure waveform at the femoral site (using a partially inflated custom blood pressure cuff) and the carotid site (using hand -held applanation tonometry) were measured simultaneously. Pulse wave analysis was performed on the central aortic pressure waveform as derived from the brachial pressure waveform recorded in a partially-inflated blood pressure cuff around the upper arm.

7. Number of Patients With Reported Adverse Events, Serious Adverse Events and Death [12 weeks]

   This outcome measure summarizes patients with any adverse events, serious adverse events and death.

Eligibility Criteria

Criteria

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

Key Inclusion Criteria:

• Subjects with essential hypertension, untreated or currently taking antihypertensive therapy

Key exclusion Criteria:

• women of child bearing potential (WOCBP) if not on highly effective contraception

• Malignant or severe hypertension (grade 3 of WHO classification)

• History or evidence of a secondary form of hypertension

• Transient ischemic cerebral attack (TIA) during the 12 months prior to screening or any history of stroke.

• Previous or current diagnosis of heart failure (New York Heart Association Class II-IV).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Berlin		Germany	10117
2	Novartis Investigative Site	Erlangen		Germany	91054
3	Novartis Investigative Site	Basel		Switzerland	4031
4	Novartis Investigative Site	Glasgow	Scotland	United Kingdom	G12 8TA

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01870739
• Other Study ID Numbers: CLCZ696A2224; 2012-005720-15
• First Posted: Jun 6, 2013
• Last Update Posted: Jan 5, 2021
• Last Verified: Mar 1, 2019

• Keywords provided by Novartis Pharmaceuticals: LCZ696,; Hypertension,; Aortic stiffness,; Central blood pressure,; Cardiovascular MRI
• Additional relevant MeSH terms: Hypertension; Amlodipine; Valsartan; Olmesartan; Olmesartan Medoxomil; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	A total of 115 patients were enrolled. One patient was discontinued after randomization before receiving any dose of study randomized medication. A total of 114 patients received study randomized medication

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
Period Title: Single Drug Treatment (12 Weeks)
STARTED	57	57
Initiation Dose Completed	57	56
Maintenance Dose Started	57	56
COMPLETED	54	53
NOT COMPLETED	3	4
Period Title: Single Drug Treatment (12 Weeks)
STARTED	54	53
COMPLETED	51	51
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan	Total
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Total of all reporting groups
Overall Participants	57	57	114
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.5 (7.8)	59.2 (13.1)	59.8 (10.7)
Sex: Female, Male (Count of Participants)
Female	20 35.1%	17 29.8%	37 32.5%
Male	37 64.9%	40 70.2%	77 67.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Ascending Aorta Distensibility at 52 Week
Description	Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Ascending aorta distensibility was one of the 3 components for measuring local arota distensibility.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
Measure Participants	49	53
Least Squares Mean (Standard Error) [10^(-3) x mmHg^(-1)]	0.269 (0.1283)	0.330 (0.1233)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sacubitril/Valsartan (LCZ696), Olmesartan
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7324
	Comments
	Method	Linear Model
	Comments	Treatment as fixed effect and corresponding baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0616
	Confidence Interval	(2-Sided) 95%; -0.4178 to 0.2947
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in Proximal Descending Aorta Distensibility at 52 Weeks
Description	Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Proximal descending aorta distensibility was one of the 3 components for measuring local arota distensibility.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
Measure Participants	49	53
Least Squares Mean (Standard Error) [10^(-3) x mmHg^(-1)]	0.510 (0.1528)	0.547 (0.1469)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sacubitril/Valsartan (LCZ696), Olmesartan
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.8614
	Comments
	Method	Linear Model
	Comments	Treatment as a fixed effect and corresponding baseline as a covariate
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0371
	Confidence Interval	(2-Sided) 95%; -0.4582 to 0.3839
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline in Distal Descending Aorta Distensibility at 52 Weeks
Description	Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Distal descending aorta distensibility was one of the 3 components for measuring local arota distensibility.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
Measure Participants	49	53
Least Squares Mean (Standard Error) [10^(-3) x mmHg^(-1)]	0.417 (0.2242)	0.498 (0.2156)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sacubitril/Valsartan (LCZ696), Olmesartan
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7946
	Comments
	Method	Linear Model
	Comments	Treatment as a fixed effect and corresponding baseline as a covariate
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0812
	Confidence Interval	(2-Sided) 95%; -0.6987 to 0.5362
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Local Aortic Strain at 52 Weeks
Description	Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic strain. Local aortic strain was measured by assessing ascending aorta strain, proximal descending aorta strain and distal descending aorta strain.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
Measure Participants	49	53
Ascending Aorta Strain	-0.830 (0.7903)	0.453 (0.7598)
Proximal Descending Aorta Strain	-0.284 (0.8940)	-0.066 (0.8596)
Distal Descending Aorta Strain	-1.092 (1.0956)	0.225 (1.0533)

5. Secondary Outcome

Title	Change From Baseline in Regional Aortic Pulse Wave Velocity at 52 Weeks
Description	Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of regional aortic pulse wave velocity.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
Measure Participants	49	53
Least Squares Mean (Standard Error) [meters per second (m/s)]	-2.086 (0.5029)	-1.085 (0.4835)

6. Secondary Outcome

Title	Change From Baseline in Central Blood Pressure at 52 Weeks
Description	Central blood pressure was determined by measuring central systolic blood pressure , diastolic blood pressure and pulse pressure.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
Measure Participants	50	50
Central systolic blood pressure	-16.655 (1.4968)	-13.625 (1.4968)
Central diastolic blood pressure	-10.318 (1.0578)	-10.432 (1.0578)
Central pulse pressure	-6.539 (0.9428)	-3.041 (0.9428)

7. Secondary Outcome

Title	Change From Baseline in Augmentation Pressure at 52 Weeks
Description	Augmentation pressure is the added pressure during systole due to wave reflection.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis.

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
Measure Participants	50	50
Least Squares Mean (Standard Error) [mmHg]	-2.443 (0.5950)	-1.437 (0.5950)

8. Secondary Outcome

Title	Change From Baseline in Augmentation Index at 52 Weeks
Description	Augmentation index (Alx) is the percentage of the central pulse pressure due to wave reflection.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
Measure Participants	50	50
Least Squares Mean (Standard Error) [percent]	-2.385 (1.1805)	-1.515 (1.1805)

9. Secondary Outcome

Title	Change From Baseline in Carotid-femoral Pulse Wave Velocity at 52 Weeks
Description	For pulse wave velocity calculation, the pressure waveform at the femoral site (using a partially inflated custom blood pressure cuff) and the carotid site (using hand -held applanation tonometry) were measured simultaneously. Pulse wave analysis was performed on the central aortic pressure waveform as derived from the brachial pressure waveform recorded in a partially-inflated blood pressure cuff around the upper arm.
Time Frame	Baseline, 52 weeks

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set: All patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data. Patients with both baseline and week 52 data were included in this analysis

Arm/Group Title	Sacubitril/Valsartan (LCZ696)	Olmesartan
Arm/Group Description	LCZ696 based treatment strategy (LCZ696 200 mg for 2 weeks as initiation dose, LCZ696 400 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)	Olmesartan based treatment strategy (olmesartan 20 mg for 2 weeks as initiation dose, olmesartan 40 mg for additional 50 weeks as maintenance dose. Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target)
Measure Participants	50	50
Least Squares Mean (Standard Error) [meters per second (m/s)]	-0.428 (0.1663)	-0.434 (0.1663)

10. Secondary Outcome

Title	Number of Patients With Reported Adverse Events, Serious Adverse Events and Death
Description	This outcome measure summarizes patients with any adverse events, serious adverse events and death.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Safety analysis set: All patients that received study drug

Arm/Group Title	Initiation Dose : Sacubitril/Valsartan (LCZ696 200mg)	Initiation Dose: Olmesartan 20mg	Maintenance Dose: Sacubitril/Valsartan (LCZ696 400mg)	Maintenance Dose: Olmesartan 40 mg	Sacubitril/Valsartan (LCZ696 400mg) +/- Amlodipine	Olmesartan 40mg +/- Amlodipine
Arm/Group Description	Patients received LCZ696 200 mg for 2 weeks as initiation dose for 2 weeks	Patients received olmesartan 20 mg for 2 weeks as initiation dose for 2 weeks	After 2 weeks on initiation dose, patients were dosed at the maintenance dose level of LCZ696 400 mg for 10 weeks	After 2 weeks on initiation dose, patients were dosed at the maintenance dose level of olmesartan 40 mg for 10 weeks	Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target	Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target
Measure Participants	57	57	57	56	54	53
Any Adverse events	13	16	21	28	31	38
Serious Adverse Events	0	2	0	2	6	5
Death	0	0	0	0	0	0

Adverse Events

Arm/Group Title	Initiation Dose : Sacubitril/Valsartan (LCZ696 200mg)		Initiation Dose: Olmesartan 20mg		Maintenance Dose: Sacubitril/Valsartan (LCZ696 400mg)		Maintenance Dose: Olmesartan 40 mg		Sacubitril/Valsartan (LCZ696 400mg) +/- Amlodipine		Olmesartan 40mg +/- Amlodipine
Arm/Group Description	Patients received LCZ696 200 mg for 2 weeks as initiation dose for 2 weeks		Patients received olmesartan 20 mg for 2 weeks as initiation dose for 2 weeks		After 2 weeks on initiation dose, patients were dosed at the maintenance dose level of LCZ696 400 mg for 10 weeks		After 2 weeks on initiation dose, patients were dosed at the maintenance dose level of olmesartan 40 mg for 10 weeks		Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target		Optional amlodipine 2.5 to 10 mg add-on after Week 12 to reach blood pressure target
All Cause Mortality
	Initiation Dose : Sacubitril/Valsartan (LCZ696 200mg)		Initiation Dose: Olmesartan 20mg		Maintenance Dose: Sacubitril/Valsartan (LCZ696 400mg)		Maintenance Dose: Olmesartan 40 mg		Sacubitril/Valsartan (LCZ696 400mg) +/- Amlodipine		Olmesartan 40mg +/- Amlodipine
	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)
Serious Adverse Events
	Initiation Dose : Sacubitril/Valsartan (LCZ696 200mg)		Initiation Dose: Olmesartan 20mg		Maintenance Dose: Sacubitril/Valsartan (LCZ696 400mg)		Maintenance Dose: Olmesartan 40 mg		Sacubitril/Valsartan (LCZ696 400mg) +/- Amlodipine		Olmesartan 40mg +/- Amlodipine
	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	0/57 (0%)		2/57 (3.5%)		0/57 (0%)		2/56 (3.6%)		6/54 (11.1%)		5/53 (9.4%)
Gastrointestinal disorders
Enterocolitis	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		0/53 (0%)
Inguinal hernia	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		0/53 (0%)
General disorders
Fat necrosis	0/57 (0%)		0/57 (0%)		0/57 (0%)		1/56 (1.8%)		0/54 (0%)		0/53 (0%)
Nodule	0/57 (0%)		0/57 (0%)		0/57 (0%)		1/56 (1.8%)		0/54 (0%)		0/53 (0%)
Infections and infestations
Appendicitis	0/57 (0%)		0/57 (0%)		0/57 (0%)		1/56 (1.8%)		0/54 (0%)		0/53 (0%)
Gastroenteritis	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		1/53 (1.9%)
Injury, poisoning and procedural complications
Abdominal injury	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		0/53 (0%)
Fall	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		0/53 (0%)
Road traffic accident	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		0/54 (0%)		1/53 (1.9%)
Tendon rupture	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		0/54 (0%)		2/53 (3.8%)
Metabolism and nutrition disorders
Dehydration	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		0/53 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		0/53 (0%)
Intraductal proliferative breast lesion	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		0/53 (0%)
Metastases to bone	0/57 (0%)		1/57 (1.8%)		0/57 (0%)		0/56 (0%)		0/54 (0%)		0/53 (0%)
Prostate cancer metastatic	0/57 (0%)		1/57 (1.8%)		0/57 (0%)		0/56 (0%)		0/54 (0%)		0/53 (0%)
Nervous system disorders
Syncope	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		0/53 (0%)
Renal and urinary disorders
Acute kidney injury	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		0/54 (0%)		1/53 (1.9%)
Haematuria	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		0/54 (0%)		1/53 (1.9%)
Vascular disorders
Hypertension	0/57 (0%)		1/57 (1.8%)		0/57 (0%)		0/56 (0%)		0/54 (0%)		0/53 (0%)
Hypertensive crisis	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		0/54 (0%)		1/53 (1.9%)
Other (Not Including Serious) Adverse Events
	Initiation Dose : Sacubitril/Valsartan (LCZ696 200mg)		Initiation Dose: Olmesartan 20mg		Maintenance Dose: Sacubitril/Valsartan (LCZ696 400mg)		Maintenance Dose: Olmesartan 40 mg		Sacubitril/Valsartan (LCZ696 400mg) +/- Amlodipine		Olmesartan 40mg +/- Amlodipine
	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	3/57 (5.3%)		6/57 (10.5%)		10/57 (17.5%)		14/56 (25%)		16/54 (29.6%)		24/53 (45.3%)
General disorders
Oedema peripheral	0/57 (0%)		0/57 (0%)		1/57 (1.8%)		0/56 (0%)		1/54 (1.9%)		4/53 (7.5%)
Infections and infestations
Influenza	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		3/53 (5.7%)
Nasopharyngitis	0/57 (0%)		2/57 (3.5%)		4/57 (7%)		5/56 (8.9%)		11/54 (20.4%)		10/53 (18.9%)
Investigations
Blood creatine phosphokinase increased	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		0/54 (0%)		3/53 (5.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/57 (0%)		0/57 (0%)		0/57 (0%)		0/56 (0%)		1/54 (1.9%)		3/53 (5.7%)
Back pain	1/57 (1.8%)		0/57 (0%)		0/57 (0%)		5/56 (8.9%)		1/54 (1.9%)		5/53 (9.4%)
Nervous system disorders
Dizziness	1/57 (1.8%)		2/57 (3.5%)		4/57 (7%)		1/56 (1.8%)		1/54 (1.9%)		0/53 (0%)
Headache	0/57 (0%)		2/57 (3.5%)		2/57 (3.5%)		6/56 (10.7%)		2/54 (3.7%)		2/53 (3.8%)
Renal and urinary disorders
Haematuria	1/57 (1.8%)		0/57 (0%)		0/57 (0%)		2/56 (3.6%)		3/54 (5.6%)		0/53 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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