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

Primary Purpose

Hypertension

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
LCZ696
Placebo
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypertension focused on measuring hypertension, blood pressure, LCZ696, dual-acting, neprilysin, nep inhibitor, vasopeptidase, angiotensin receptor, ARNi, Essential hypertension

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients must give written informed consent before any assessment is performed.
  2. Patients with mild to moderate essential hypertension, untreated or currently taking antihypertensive therapy (mean sitting diastolic blood pressure ≥ 95 mmHg and < 110 mmHg, and mean sitting systolic blood pressure ≥ 140 mmHg and < 180 mmHg).
  3. Patients must be willing and able to undergo ambulatory blood pressure monitoring for a 24-hr period at the beginning and the end of the 8-week treatment.
  4. Patient must be able to communicate and comply with all study requirements and demonstrate good medication compliance.

Exclusion Criteria:

  1. Patients with severe hypertension.
  2. Patients with history of angioedema, drug-related or otherwise
  3. Pregnant or nursing women
  4. Women of child-bearing potential , who do not use adequate birth control methods
  5. History or evidence of a secondary form of hypertension.
  6. History of angina pectoris, myocardial infarction, coronary bypass surgery, ischemic heart disease, surgical or percutaneous arterial intervention of any kind, stroke, TIA, carotid artery stenosis, aortic aneurysm, or peripheral arterial disease.
  7. Diabetes mellitus.
  8. Previous or current diagnosis of heart failure (NYHA Class II-IV).
  9. Clinically significant valvular heart disease at the time of screening.

Other protocol-defined inclusion/exclusion criteria may apply

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

LCZ696 100 mg

LCZ696 200 mg

LCZ696 400 mg

Placebo

Arm Description

LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.

LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.

LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.

Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)
Sitting BP measurements were performed at screening through the end of the study at every study visit. A negative change from baseline indicates improvement.
Change From Baseline in 24 Hour Mean Ambulatory DBP and SBP
Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. A negative change from baseline indicates improvement.
Change From Baseline in Daytime Mean Ambulatory DBP and SBP
Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. Daytime mean SBP and DBP were the averages of the hourly means between 6 am and 10 pm. A negative change from baseline indicates improvement.
Change From Baseline in Nighttime Mean Ambulatory DBP and SBP
Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. Nighttime mean SBP and DBP were the averages of the hourly means between 10 pm and 6 am. A negative change from baseline indicates improvement.
Change From Baseline in Mean Sitting Pulse Pressure
Mean sitting pulse pressure is the difference in msSBP and msDBP (msSBP - msDBP). A negative change from baseline indicates improvement.
Change From Baseline in Mean Ambulatory Pulse Pressure
Mean ambulatory pulse pressure is the difference in maSBP and maDBP (maSBP - maDBP). A negative change from baseline indicates improvement.
Number of Participants Who Achieved a Successful Response in msDBP
Successful response in msDBP is defined as msDBP <90 mmHg or a reduction ≥ 10 mmHg from baseline.
Number of Participants Who Achieved a Successful Response in msSBP
Successful response in msSBP is defined as msSBP <140 mmHg or a reduction ≥ 20 mmHg from baseline.
Number of Participants Who Achieved Successful BP Control
BP control is defined as BP < 140/90 mmHg.
Trough to Post-dosing Hour Ratio for Change From Baseline in 24-hour Mean Ambulatory DBP
Trough to post-dosing hour ratio at each post-dosing hour = [trough LSM of LCZ696 - trough LSM of placebo]/[post-dosing hour LSM of LCZ696 - post-dosing hour LSM of placebo]
Trough to Post-dosing Hour Ratio for Change From Baseline in 24-hour Mean Ambulatory SBP
Trough to post-dosing hour ratio at each post-dosing hour = [trough LSM of LCZ696 - trough LSM of placebo]/[post-dosing hour LSM of LCZ696 - post-dosing hour LSM of placebo]
Change From Week 8 to Week 9 in msDBP and msSBP After Single-blind Placebo Withdrawal at Week 8
From week 8 to week 9, participants entered a single-blind placebo withdrawal period to assess the effect of LCZ696 on blood pressure following its discontinuation. Participants, who were randomized to the LCZ696 treatment groups, were discontinued from CLCZ696 at the end of week 8 and all 4 treatment groups received single-blind placebo for 1 week post week 8. A positive change from week 8 to week 9 indicates worsening.

Full Information

First Posted
August 26, 2010
Last Updated
January 13, 2016
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01193101
Brief Title
Efficacy and Safety of LCZ696 Compared to Placebo in Patients With Essential Hypertension
Official Title
A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-ranging Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Placebo After 8 Weeks Treatment in Patients With Essential Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
January 2016
Overall Recruitment Status
Completed
Study Start Date
August 2010 (undefined)
Primary Completion Date
April 2011 (Actual)
Study Completion Date
April 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension
Keywords
hypertension, blood pressure, LCZ696, dual-acting, neprilysin, nep inhibitor, vasopeptidase, angiotensin receptor, ARNi, Essential hypertension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
389 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LCZ696 100 mg
Arm Type
Experimental
Arm Description
LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.
Arm Title
LCZ696 200 mg
Arm Type
Experimental
Arm Description
LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.
Arm Title
LCZ696 400 mg
Arm Type
Experimental
Arm Description
LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.
Intervention Type
Drug
Intervention Name(s)
LCZ696
Intervention Description
LCZ696
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
matching placebo to LCZ696
Primary Outcome Measure Information:
Title
Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP)
Description
Sitting BP measurements were performed at screening through the end of the study at every study visit. A negative change from baseline indicates improvement.
Time Frame
Baseline, 8 weeks
Secondary Outcome Measure Information:
Title
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)
Description
Sitting BP measurements were performed at screening through the end of the study at every study visit. A negative change from baseline indicates improvement.
Time Frame
Baseline, 8 weeks
Title
Change From Baseline in 24 Hour Mean Ambulatory DBP and SBP
Description
Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. A negative change from baseline indicates improvement.
Time Frame
Baseline, 8 weeks
Title
Change From Baseline in Daytime Mean Ambulatory DBP and SBP
Description
Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. Daytime mean SBP and DBP were the averages of the hourly means between 6 am and 10 pm. A negative change from baseline indicates improvement.
Time Frame
Baseline, 8 weeks
Title
Change From Baseline in Nighttime Mean Ambulatory DBP and SBP
Description
Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the average of the readings taken in the corresponding post-dosing hour at randomization and at week 8. Nighttime mean SBP and DBP were the averages of the hourly means between 10 pm and 6 am. A negative change from baseline indicates improvement.
Time Frame
Baseline, 8 weeks
Title
Change From Baseline in Mean Sitting Pulse Pressure
Description
Mean sitting pulse pressure is the difference in msSBP and msDBP (msSBP - msDBP). A negative change from baseline indicates improvement.
Time Frame
Baseline, 8 weeks
Title
Change From Baseline in Mean Ambulatory Pulse Pressure
Description
Mean ambulatory pulse pressure is the difference in maSBP and maDBP (maSBP - maDBP). A negative change from baseline indicates improvement.
Time Frame
Baseline, 8 weeks
Title
Number of Participants Who Achieved a Successful Response in msDBP
Description
Successful response in msDBP is defined as msDBP <90 mmHg or a reduction ≥ 10 mmHg from baseline.
Time Frame
8 weeks
Title
Number of Participants Who Achieved a Successful Response in msSBP
Description
Successful response in msSBP is defined as msSBP <140 mmHg or a reduction ≥ 20 mmHg from baseline.
Time Frame
8 weeks
Title
Number of Participants Who Achieved Successful BP Control
Description
BP control is defined as BP < 140/90 mmHg.
Time Frame
8 weeks
Title
Trough to Post-dosing Hour Ratio for Change From Baseline in 24-hour Mean Ambulatory DBP
Description
Trough to post-dosing hour ratio at each post-dosing hour = [trough LSM of LCZ696 - trough LSM of placebo]/[post-dosing hour LSM of LCZ696 - post-dosing hour LSM of placebo]
Time Frame
baseline, 8 weeks
Title
Trough to Post-dosing Hour Ratio for Change From Baseline in 24-hour Mean Ambulatory SBP
Description
Trough to post-dosing hour ratio at each post-dosing hour = [trough LSM of LCZ696 - trough LSM of placebo]/[post-dosing hour LSM of LCZ696 - post-dosing hour LSM of placebo]
Time Frame
baseline, 8 weeks
Title
Change From Week 8 to Week 9 in msDBP and msSBP After Single-blind Placebo Withdrawal at Week 8
Description
From week 8 to week 9, participants entered a single-blind placebo withdrawal period to assess the effect of LCZ696 on blood pressure following its discontinuation. Participants, who were randomized to the LCZ696 treatment groups, were discontinued from CLCZ696 at the end of week 8 and all 4 treatment groups received single-blind placebo for 1 week post week 8. A positive change from week 8 to week 9 indicates worsening.
Time Frame
8 weeks, 9 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must give written informed consent before any assessment is performed. Patients with mild to moderate essential hypertension, untreated or currently taking antihypertensive therapy (mean sitting diastolic blood pressure ≥ 95 mmHg and < 110 mmHg, and mean sitting systolic blood pressure ≥ 140 mmHg and < 180 mmHg). Patients must be willing and able to undergo ambulatory blood pressure monitoring for a 24-hr period at the beginning and the end of the 8-week treatment. Patient must be able to communicate and comply with all study requirements and demonstrate good medication compliance. Exclusion Criteria: Patients with severe hypertension. Patients with history of angioedema, drug-related or otherwise Pregnant or nursing women Women of child-bearing potential , who do not use adequate birth control methods History or evidence of a secondary form of hypertension. History of angina pectoris, myocardial infarction, coronary bypass surgery, ischemic heart disease, surgical or percutaneous arterial intervention of any kind, stroke, TIA, carotid artery stenosis, aortic aneurysm, or peripheral arterial disease. Diabetes mellitus. Previous or current diagnosis of heart failure (NYHA Class II-IV). Clinically significant valvular heart disease at the time of screening. Other protocol-defined inclusion/exclusion criteria may apply
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Shijiazhuang
State/Province
Hebei
ZIP/Postal Code
050000
Country
China
Facility Name
Novartis Investigative Site
City
Tianjin
State/Province
Tianjin
ZIP/Postal Code
300142
Country
China
Facility Name
Novartis Investigative Site
City
Hangzhou
State/Province
Zhejiang
ZIP/Postal Code
310009
Country
China
Facility Name
Novartis Investigative Site
City
Beijing
ZIP/Postal Code
100044
Country
China
Facility Name
Novartis Investigative Site
City
Beijing
ZIP/Postal Code
100730
Country
China
Facility Name
Novartis Investigative Site
City
Chongqing
ZIP/Postal Code
400042
Country
China
Facility Name
Novartis Investigative Site
City
Yokohama-city
State/Province
Kanagawa
ZIP/Postal Code
231-0023
Country
Japan
Facility Name
Novartis Investigative Site
City
Shimotsuke-city
State/Province
Tochigi
ZIP/Postal Code
329-0498
Country
Japan
Facility Name
Novartis Investigative Site
City
Bunkyo-ku
State/Province
Tokyo
ZIP/Postal Code
113-0031
Country
Japan
Facility Name
Novartis Investigative Site
City
Bunkyo-ku
State/Province
Tokyo
ZIP/Postal Code
113-8655
Country
Japan
Facility Name
Novartis Investigative Site
City
Chiyoda-ku
State/Province
Tokyo
ZIP/Postal Code
100-0005
Country
Japan
Facility Name
Novartis Investigative Site
City
Kiyose-city
State/Province
Tokyo
ZIP/Postal Code
204-0021
Country
Japan
Facility Name
Novartis Investigative Site
City
Kunitachi
State/Province
Tokyo
ZIP/Postal Code
186-0001
Country
Japan
Facility Name
Novartis Investigative Site
City
Minato-ku
State/Province
Tokyo
ZIP/Postal Code
105-7390
Country
Japan
Facility Name
Novartis Investigative Site
City
Minato-ku
State/Province
Tokyo
ZIP/Postal Code
108-0075
Country
Japan
Facility Name
Novartis Investigative Site
City
Ota-ku
State/Province
Tokyo
ZIP/Postal Code
143-0023
Country
Japan
Facility Name
Novartis Investigative Site
City
Shinagawa-ku
State/Province
Tokyo
ZIP/Postal Code
141-0032
Country
Japan
Facility Name
Novartis Investigative Site
City
Shinagawa-ku
State/Province
Tokyo
ZIP/Postal Code
142-0053
Country
Japan
Facility Name
Novartis Investigative Site
City
Shinagawa-ku
State/Province
Tokyo
ZIP/Postal Code
142-0063
Country
Japan
Facility Name
Novartis Investigative Site
City
Toshima-ku
State/Province
Tokyo
ZIP/Postal Code
171-0021
Country
Japan
Facility Name
Novartis Investigative Site
City
Bucheon
State/Province
Gyeonggi-do
ZIP/Postal Code
424-717
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Korea
ZIP/Postal Code
137-701
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Koyang
State/Province
Kyunggi
ZIP/Postal Code
410-719
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Daegu
ZIP/Postal Code
705-703
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
150-950
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
152-703
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Changhua
ZIP/Postal Code
500
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Taichung
ZIP/Postal Code
40447
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Taipei
ZIP/Postal Code
10002
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Taipei
ZIP/Postal Code
10449
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Taipei
ZIP/Postal Code
114
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Bangkok
ZIP/Postal Code
10400
Country
Thailand
Facility Name
Novartis Investigative Site
City
Bangkok
ZIP/Postal Code
10700
Country
Thailand
Facility Name
Novartis Investigative Site
City
Chiang Mai
ZIP/Postal Code
50200
Country
Thailand

12. IPD Sharing Statement

Citations:
PubMed Identifier
26280447
Citation
Andersen MB, Simonsen U, Wehland M, Pietsch J, Grimm D. LCZ696 (Valsartan/Sacubitril)--A Possible New Treatment for Hypertension and Heart Failure. Basic Clin Pharmacol Toxicol. 2016 Jan;118(1):14-22. doi: 10.1111/bcpt.12453. Epub 2015 Sep 4.
Results Reference
derived
PubMed Identifier
24446062
Citation
Kario K, Sun N, Chiang FT, Supasyndh O, Baek SH, Inubushi-Molessa A, Zhang Y, Gotou H, Lefkowitz M, Zhang J. Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study. Hypertension. 2014 Apr;63(4):698-705. doi: 10.1161/HYPERTENSIONAHA.113.02002. Epub 2014 Jan 20.
Results Reference
derived

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

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