Safety and Tolerability and Efficacy of LCZ696 in Japanese Severe Hypertensive Patients

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01646671
• Collaborator: (none)
• Enrollment: 35
• Locations: 9
• Arms: 3
• Duration (Months): 7.1
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This study assessed the safety, tolerability, and efficacy of LCZ696 in severe hypertensive Japanese patients

Condition or Disease	Intervention/Treatment	Phase
Severe Hypertension	Drug: LCZ696; Drug: LCZ696; Drug: LCZ696	Phase 3

Detailed Description

Summaries for treatment-emergent adverse events, serious adverse events and death were provided by the following actual treatment regimen (actual treatment patients received) in addition to all patients: LCZ696 200mg, 400mg, 400mg+other hypertensive medications.

Summaries for others than above were provided by the following treatment regimen (determined by the maximal treatment patients received) in addition to all patients: LCZ696 200mg, 400mg, 400mg+other hypertensive medications.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Open Label Study for Evaluation of the Safety, Tolerability and Efficacy of 8-week Treatment With LCZ696 in Japanese Patients With Severe Hypertension
• Study Start Date: Jul 1, 2012
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 200 mg All participants were started on LCZ696 200 mg once daily on day 1. Participants who achieved mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and for the duration of the study continued at 200 mg LCZ696 once daily.	Drug: LCZ696; LCZ696 200 mg tablet once daily
Experimental: LCZ696 400 mg All participants were started on LCZ696 200 mg once daily on day 1. For participants who did not achieve mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4, and did not have any signs of safety concerns, the LCZ696 dose was increased to 400 mg once daily.	Drug: LCZ696; 2 tablets of LCZ696 200 mg once daily titrated up from 1 tablet of 200 mg once daily
Experimental: LCZ696 400 mg plus other hypertension (HTN) medications All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study.	Drug: LCZ696; 2 tablets of LCZ696 200 mg once daily titrated up from 1 tablet of 200 mg once daily plus other HTN medications

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Adverse Events (AEs), Serious Adverse Events and Deaths [Week 8]

   Adverse events, serious adverse events deaths were monitored from screening to week 8.

Secondary Outcome Measures

1. Change From Baseline in msSBP and msDBP at Week 8 [Baseline, 8 weeks]

   Sitting BP measurements were performed at screening through the end of study at every visit. Four separate sitting BP measurements were obtained with a full two-minute interval between measurements. The 4 measurements were summed and averaged, and then the baseline BP value was subtracted from the average value to get the change from baseline value.

2. Percentage of Participants With Successful Blood Pressure (BP) Control in msSBP/msDBP at End of Study [8 weeks]

   Successful BP control in patients with severe hypertension at the end of study treatment was defined as follows: msSBP/msDBP< 140/90 mmHg.

3. Percentage of Participants Achieving Successful msSBP Control at End of Study [8 weeks]

   Successful msSBP control in patients with severe hypertension at the end of study treatment was defined as msSBP <140 mmHg.

4. Percentage of Participants Achieving Successful msDBP Control at End of Study [8 weeks]

   Successful msDBP control in patients with severe hypertension at the end of study treatment was defined as msDBP < 90 mmHg.

5. Percentage of Participants With SBP Response at End of Study [Baseline, 8 weeks]

   SBP response was defined as <140 mmHg or a reduction ≥ 20 mmHg from baseline.

6. Percentage of Participants With DBP Response at End of Study [Baseline, 8 weeks]

   DBP response was defined as <90 mmHg or a reduction ≥ 10 mmHg from baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Satisfy office msSBP ≥180 mmHg or office msDBP ≥110 mmHg at baseline

Exclusion Criteria:

• Patients show msSBP ≥220 mmHg and/or msDBP ≥120 mmHg

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

• Patients unwilling or not able to discontinue safely the use of current antihypertensive medications during the study, as required by the protocol.

• Patients have significant cardiovascular co-morbidities

• Patients who previously entered a LCZ696 study and had been randomized or enrolled into the active drug treatment epoch.

Other protocol defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	231-0023
2	Novartis Investigative Site	Kyoto-city	Kyoto	Japan	606-8507
3	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-0031
4	Novartis Investigative Site	Hachioji-city	Tokyo	Japan	192-0918
5	Novartis Investigative Site	Minato-ku	Tokyo	Japan	105-7390
6	Novartis Investigative Site	Minato-ku	Tokyo	Japan	108-0075
7	Novartis Investigative Site	Ota-ku	Tokyo	Japan	143-0023
8	Novartis Investigative Site	Shibuya-ku	Tokyo	Japan	150-0002
9	Novartis Investigative Site	Shinagawa-ku	Tokyo	Japan	141-0032

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: NCT01646671
• Other Study ID Numbers: CLCZ696A1305
• First Posted: Jul 20, 2012
• Last Update Posted: Oct 23, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Novartis Pharmaceuticals: Hypertension, Severe, LCZ696
• Additional relevant MeSH terms: Hypertension; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ696 400 mg Plus Other Hypertension (HTN) Medications
Arm/Group Description	All participants were started on LCZ696 200 mg once daily on day 1. Participants who achieved mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and for the duration of the study continued at 200 mg LCZ696 once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who did not achieve mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4, and did not have any signs of safety concerns, the LCZ696 dose was increased to 400 mg once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study.
Period Title: Overall Study
STARTED	3	11	21
COMPLETED	3	11	21
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ696 400 mg Plus Other Hypertension (HTN) Medications	Total
Arm/Group Description	All participants were started on LCZ696 200 mg once daily on day 1. Participants who achieved mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and for the duration of the study continued at 200 mg LCZ696 once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who did not achieve mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4, and did not have any signs of safety concerns, the LCZ696 dose was increased to 400 mg once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study.	Total of all reporting groups
Overall Participants	3	11	21	35
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	48.0 (4.0)	56.0 (12.24)	49.3 (7.57)	51.3 (9.45)
Sex: Female, Male (Count of Participants)
Female	0 0%	2 18.2%	0 0%	2 5.7%
Male	3 100%	9 81.8%	21 100%	33 94.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events (AEs), Serious Adverse Events and Deaths
Description	Adverse events, serious adverse events deaths were monitored from screening to week 8.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

AE analysis was determined by actual treatment, i.e. the LCZ696 dose and use of newly introduced anti-HTN medication/dose escalation of base anti-HTN medication on the day in which the corresponding summary was targeting. Participants could be counted in more than one category. Other safety analysis was determined by the maximum treatment.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ696 400 mg Plus Other Hypertension (HTN) Medications	Total Participants
Arm/Group Description	All participants were started on LCZ696 200 mg once daily on day 1. Participants who achieved mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and for the duration of the study continued at 200 mg LCZ696 once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who did not achieve mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4, and did not have any signs of safety concerns, the LCZ696 dose was increased to 400 mg once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study.	All participants who were treated
Measure Participants	35	32	21	35
Adverse Events (serious and non-serious)	20.0 666.7%	12.5 113.6%	33.3 158.6%	48.6 138.9%
Serious Adverse Events	2.9 96.7%	0 0%	0 0%	2.9 8.3%
Deaths	0 0%	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Change From Baseline in msSBP and msDBP at Week 8
Description	Sitting BP measurements were performed at screening through the end of study at every visit. Four separate sitting BP measurements were obtained with a full two-minute interval between measurements. The 4 measurements were summed and averaged, and then the baseline BP value was subtracted from the average value to get the change from baseline value.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: included all patients who entered the treatment epoch. This set was determined by the maximum treatment patients received, i.e. combination of the highest LCZ696 dose and use of newly introduced anti-HTN medication/dose escalation of base anti-HTN medication during the treatment epoch.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ696 400 mg Plus Other Hypertension (HTN) Medications	Total Participants
Arm/Group Description	All participants were started on LCZ696 200 mg once daily on day 1. Participants who achieved mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and for the duration of the study continued at 200 mg LCZ696 once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who did not achieve mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4, and did not have any signs of safety concerns, the LCZ696 dose was increased to 400 mg once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study.	All participants who were treated
Measure Participants	3	11	21	35
msSBP	-48.83 (11.730)	-30.34 (15.054)	-35.98 (15.229)	-35.31 (15.348)
msDBP	-34.25 (7.378)	-16.98 (7.394)	-23.08 (8.514)	-22.12 (9.167)

3. Secondary Outcome

Title	Percentage of Participants With Successful Blood Pressure (BP) Control in msSBP/msDBP at End of Study
Description	Successful BP control in patients with severe hypertension at the end of study treatment was defined as follows: msSBP/msDBP< 140/90 mmHg.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: included all patients who entered the treatment epoch. This set was determined by the maximum treatment patients received, i.e. combination of the highest LCZ696 dose and use of newly introduced anti-HTN medication/dose escalation of base anti-HTN medication during the treatment epoch.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ696 400 mg Plus Other Hypertension (HTN) Medications	Total Participants
Arm/Group Description	All participants were started on LCZ696 200 mg once daily on day 1. Participants who achieved mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and for the duration of the study continued at 200 mg LCZ696 once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who did not achieve mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4, and did not have any signs of safety concerns, the LCZ696 dose was increased to 400 mg once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study.	All participants who were treated
Measure Participants	3	11	21	35
Number [Percentage of Participants]	66.7 2223.3%	18.2 165.5%	47.6 226.7%	40.0 114.3%

4. Secondary Outcome

Title	Percentage of Participants Achieving Successful msSBP Control at End of Study
Description	Successful msSBP control in patients with severe hypertension at the end of study treatment was defined as msSBP <140 mmHg.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: included all patients who entered the treatment epoch. This set was determined by the maximum treatment patients received, i.e. combination of the highest LCZ696 dose and use of newly introduced anti-HTN medication/dose escalation of base anti-HTN medication during the treatment epoch.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ696 400 mg Plus Other Hypertension (HTN) Medications	Total Participants
Arm/Group Description	All participants were started on LCZ696 200 mg once daily on day 1. Participants who achieved mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and for the duration of the study continued at 200 mg LCZ696 once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who did not achieve mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4, and did not have any signs of safety concerns, the LCZ696 dose was increased to 400 mg once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study.	All participants who were treated
Measure Participants	3	11	21	35
Number [Percentage of Participants]	100 3333.3%	45.5 413.6%	66.7 317.6%	62.9 179.7%

5. Secondary Outcome

Title	Percentage of Participants Achieving Successful msDBP Control at End of Study
Description	Successful msDBP control in patients with severe hypertension at the end of study treatment was defined as msDBP < 90 mmHg.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: included all patients who entered the treatment epoch. This set was determined by the maximum treatment patients received, i.e. combination of the highest LCZ696 dose and use of newly introduced anti-HTN medication/dose escalation of base anti-HTN medication during the treatment epoch.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ696 400 mg Plus Other Hypertension (HTN) Medications	Total Participants
Arm/Group Description	All participants were started on LCZ696 200 mg once daily on day 1. Participants who achieved mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and for the duration of the study continued at 200 mg LCZ696 once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who did not achieve mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4, and did not have any signs of safety concerns, the LCZ696 dose was increased to 400 mg once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study.	All participants who were treated
Measure Participants	3	11	21	35
Number [Percentage of Participants]	66.7 2223.3%	36.4 330.9%	52.4 249.5%	48.6 138.9%

6. Secondary Outcome

Title	Percentage of Participants With SBP Response at End of Study
Description	SBP response was defined as <140 mmHg or a reduction ≥ 20 mmHg from baseline.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: included all patients who entered the treatment epoch. This set was determined by the maximum treatment patients received, i.e. combination of the highest LCZ696 dose and use of newly introduced anti-HTN medication/dose escalation of base anti-HTN medication during the treatment epoch.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ696 400 mg Plus Other Hypertension (HTN) Medications	Total Participants
Arm/Group Description	All participants were started on LCZ696 200 mg once daily on day 1. Participants who achieved mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and for the duration of the study continued at 200 mg LCZ696 once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who did not achieve mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4, and did not have any signs of safety concerns, the LCZ696 dose was increased to 400 mg once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study.	All participants who were treated
Measure Participants	3	11	21	35
Number [Percentage of Participants]	100 3333.3%	81.8 743.6%	85.7 408.1%	85.7 244.9%

7. Secondary Outcome

Title	Percentage of Participants With DBP Response at End of Study
Description	DBP response was defined as <90 mmHg or a reduction ≥ 10 mmHg from baseline.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: included all patients who entered the treatment epoch. This set was determined by the maximum treatment patients received, i.e. combination of the highest LCZ696 dose and use of newly introduced anti-HTN medication/dose escalation of base anti-HTN medication during the treatment epoch.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ696 400 mg Plus Other Hypertension (HTN) Medications	Total Participants
Arm/Group Description	All participants were started on LCZ696 200 mg once daily on day 1. Participants who achieved mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and for the duration of the study continued at 200 mg LCZ696 once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who did not achieve mean sitting diastolic blood pressure (msDBP) of < 100 mmHg and mean sitting systolic blood pressure (msSBP) of < 160 mmHg at week 2 or a msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4, and did not have any signs of safety concerns, the LCZ696 dose was increased to 400 mg once daily.	All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP < 90 mmHg and msSBP < 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study.	All participants who were treated
Measure Participants	3	11	21	35
Number [Percentage of Participants]	100 3333.3%	100 909.1%	100 476.2%	100 285.7%

Adverse Events

Adverse Event Reporting Description	SAE and other AE analyses were determined by actual treatment, i.e. the LCZ696 dose and use of newly introduced anti-HTN medication/dose escalation of base anti-HTN medication on the day in which the corresponding summary was targeting. Participants could be counted in more than one category.
Arm/Group Title	LCZ 200 mg		LCZ 400 mg		LCZ 400 mg + Other HTN Medications		Total Participants
Arm/Group Description	LCZ 200 mg		LCZ 400 mg		LCZ 400 mg + other HTN medications		All participants who were treated
All Cause Mortality
	LCZ 200 mg		LCZ 400 mg		LCZ 400 mg + Other HTN Medications		Total Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	LCZ 200 mg		LCZ 400 mg		LCZ 400 mg + Other HTN Medications		Total Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/35 (2.9%)		0/32 (0%)		0/21 (0%)		1/35 (2.9%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	1/35 (2.9%)		0/32 (0%)		0/21 (0%)		1/35 (2.9%)
ASPARTATE AMINOTRANSFERASE INCREASED	1/35 (2.9%)		0/32 (0%)		0/21 (0%)		1/35 (2.9%)
Other (Not Including Serious) Adverse Events
	LCZ 200 mg		LCZ 400 mg		LCZ 400 mg + Other HTN Medications		Total Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/35 (11.4%)		2/32 (6.3%)		5/21 (23.8%)		10/35 (28.6%)
Infections and infestations
NASOPHARYNGITIS	1/35 (2.9%)		2/32 (6.3%)		3/21 (14.3%)		6/35 (17.1%)
Investigations
BLOOD CREATINE PHOSPHOKINASE INCREASED	2/35 (5.7%)		0/32 (0%)		1/21 (4.8%)		3/35 (8.6%)
Metabolism and nutrition disorders
HYPERURICAEMIA	1/35 (2.9%)		0/32 (0%)		1/21 (4.8%)		2/35 (5.7%)

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.