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

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

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: LCZ696; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 389
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100044
    • Novartis Investigative Site
  • Beijing, China, 100730
    • Novartis Investigative Site
  • Chongqing, China, 400042
    • Novartis Investigative Site
  • Hebei
    • Shijiazhuang, Hebei, China, 050000
      • Novartis Investigative Site
  • Tianjin
    • Tianjin, Tianjin, China, 300142
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310009
      • Novartis Investigative Site
• Japan
  • Kanagawa
    • Yokohama-city, Kanagawa, Japan, 231-0023
      • Novartis Investigative Site
  • Tochigi
    • Shimotsuke-city, Tochigi, Japan, 329-0498
      • Novartis Investigative Site
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-0031
      • Novartis Investigative Site
    • Bunkyo-ku, Tokyo, Japan, 113-8655
      • Novartis Investigative Site
    • Chiyoda-ku, Tokyo, Japan, 100-0005
      • Novartis Investigative Site
    • Kiyose-city, Tokyo, Japan, 204-0021
      • Novartis Investigative Site
    • Kunitachi, Tokyo, Japan, 186-0001
      • Novartis Investigative Site
    • Minato-ku, Tokyo, Japan, 105-7390
      • Novartis Investigative Site
    • Minato-ku, Tokyo, Japan, 108-0075
      • Novartis Investigative Site
    • Ota-ku, Tokyo, Japan, 143-0023
      • Novartis Investigative Site
    • Shinagawa-ku, Tokyo, Japan, 141-0032
      • Novartis Investigative Site
    • Shinagawa-ku, Tokyo, Japan, 142-0053
      • Novartis Investigative Site
    • Shinagawa-ku, Tokyo, Japan, 142-0063
      • Novartis Investigative Site
    • Toshima-ku, Tokyo, Japan, 171-0021
      • Novartis Investigative Site
• Korea, Republic of
  • Daegu, Korea, Republic of, 705-703
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 150-950
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 152-703
    • Novartis Investigative Site
  • Gyeonggi-do
    • Bucheon, Gyeonggi-do, Korea, Republic of, 424-717
      • Novartis Investigative Site
  • Korea
    • Seoul, Korea, Korea, Republic of, 137-701
      • Novartis Investigative Site
  • Kyunggi
    • Koyang, Kyunggi, Korea, Republic of, 410-719
      • Novartis Investigative Site
• Taiwan
  • Changhua, Taiwan, 500
    • Novartis Investigative Site
  • Taichung, Taiwan, 40447
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 114
    • Novartis Investigative Site
  • Taipei, Taiwan, 10449
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Chiang Mai, Thailand, 50200
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: LCZ696; LCZ696; Drug: Placebo; matching placebo to LCZ696
Experimental: 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.	Drug: LCZ696; LCZ696; Drug: Placebo; matching placebo to LCZ696
Experimental: 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.	Drug: LCZ696; LCZ696; Drug: Placebo; matching placebo to LCZ696
Placebo Comparator: Placebo; Placebo daily for 8 weeks during DB treatment, and then single-blind placebo for 1 week.	Drug: Placebo; matching placebo to LCZ696

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: August 26, 2010
• First Submitted That Met QC Criteria: August 30, 2010
• First Posted (Estimate): September 1, 2010

Study Record Updates

• Last Update Posted (Estimate): February 15, 2016
• Last Update Submitted That Met QC Criteria: January 13, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: hypertension; blood pressure; Essential hypertension; LCZ696; dual-acting; neprilysin; nep inhibitor; vasopeptidase; angiotensin receptor; ARNi
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Molecular Mechanisms of Pharmacological Action; Angiotensin Receptor Antagonists; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696A2219