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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01193101

Enrollment

389

Registered

2010-09-01

Start date

2010-08-31

Completion date

2011-04-30

Last updated

2016-02-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypertension

Keywords

hypertension, blood pressure, LCZ696, dual-acting, neprilysin, nep inhibitor, vasopeptidase, angiotensin receptor, ARNi, Essential hypertension

Brief summary

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

Interventions

DRUGLCZ696

LCZ696

DRUGPlacebo

matching placebo to LCZ696

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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/

Design outcomes

Primary

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

Secondary

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

Countries

China, Japan, South Korea, Taiwan, Thailand

Participant flow

Recruitment details

This study comprised 3 periods: a 4 week washout and placebo run-in period, an 8 week randomized, double-blind period and a 1 week single-blind, placebo withdrawal period.

Pre-assignment details

In the run-in period, 457 participants were enrolled. Of the 457 participants, 389 participants were eligible for randomization and randomized in a 1:1:1:1 ratio to each treatment group.

Participants by arm

Arm	Count
LCZ696 100 mg LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	100
LCZ696 200 mg LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week.	101
LCZ696 400 mg LCZ696 200 mg LCZ696 plus placebo for one week, then titrated up to 400 mg plus placebo for the remaining 7 weeks during DB treatment, and then single-blind placebo for one week.	96
Placebo Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.	92
Total	389

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Abnormal test procedure results	0	1	0	0
Overall Study	Administrative problems	0	0	1	0
Overall Study	Adverse Event	0	1	1	3
Overall Study	Lack of Efficacy	3	1	0	8
Overall Study	Withdrawal by Subject	2	4	1	1

Baseline characteristics

Characteristic	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Placebo	Total
Age, Continuous	52.5 Years STANDARD_DEVIATION 10.03	52.1 Years STANDARD_DEVIATION 8.82	50.9 Years STANDARD_DEVIATION 9.81	50.9 Years STANDARD_DEVIATION 10.65	51.6 Years STANDARD_DEVIATION 9.82
Sex: Female, Male Female	40 Participants	27 Participants	23 Participants	24 Participants	114 Participants
Sex: Female, Male Male	60 Participants	74 Participants	73 Participants	68 Participants	275 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	16 / 100	11 / 101	14 / 96	15 / 92
serious Total, serious adverse events	0 / 100	1 / 101	2 / 96	0 / 92

Outcome results

Primary

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.

Time frame: Baseline, 8 weeks