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

Study Overview
=================
Brief Summary
-----------------
This study is a phase 2 study 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

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: LCZ696
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCZ696 100 mg<br>LCZ696 100 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week. | Drug: LCZ696<br>* LCZ696<br>Drug: Placebo<br>* matching placebo to LCZ696<br>|
| Experimental: LCZ696 200 mg<br>LCZ696 200 mg plus placebo daily during double blind (DB) treatment for 8 weeks and then single-blind placebo for one week. | Drug: LCZ696<br>* LCZ696<br>Drug: Placebo<br>* matching placebo to LCZ696<br>|
| Experimental: LCZ696 400 mg<br>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. | Drug: LCZ696<br>* LCZ696<br>Drug: Placebo<br>* matching placebo to LCZ696<br>|
| Placebo Comparator: Placebo<br>Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week. | Drug: Placebo<br>* matching placebo to LCZ696<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 8 weeks | 
| 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. | Baseline, 8 weeks | 
| 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. | Baseline, 8 weeks | 
| 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. | Baseline, 8 weeks | 
| 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. | Baseline, 8 weeks | 
| 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. | Baseline, 8 weeks | 
| 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. | 8 weeks | 
| 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. | 8 weeks | 
| Number of Participants Who Achieved Successful BP Control | BP control is defined as BP < 140/90 mmHg. | 8 weeks | 
| 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] | baseline, 8 weeks | 
| 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] | baseline, 8 weeks | 
| 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. | 8 weeks, 9 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hypertension, blood pressure, LCZ696, dual-acting, neprilysin, nep inhibitor, vasopeptidase, angiotensin receptor, ARNi, Essential hypertension