Efficacy and Safety of LCZ696A in Patients With Essential Hypertension

A Multi-center, Randomized, Double-blind, Placebo and Active Controlled, Parallel Group, Dose Range Study to Evaluate the Efficacy and Safety of LCZ696 Comparatively to Valsartan, and to Evaluate AHU377 to Placebo After 8 Week Treatment in Patients With Essential Hypertension

This study was a dose-ranging efficiacy study in patients with essential hypertension to assess the blood pressure lowering effect, and safety of LCZ696 compared to valsartan and placebo. The study will also evaluate the efficacy and safety of AHU377 as compared to placebo.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: Valsartan; Drug: LCZ696; Drug: AHU377

• Study Type: Interventional
• Enrollment (Actual): 1334
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Corrientes, Argentina, W3400
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1408INH
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1416DRJ
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1425AST
      • Novartis Investigative Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000CXH
      • Novartis Investigative Site
• Canada
  • Ontario
    • Cambridge, Ontario, Canada, N1R 6V6
      • Novartis Investigative Site
    • Mississauga, Ontario, Canada, M4T 4J2
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M9W 4L6
      • Novartis Investigative Site
  • Quebec
    • Granby, Quebec, Canada, J2G 8Z9
      • Novartis Investigative Site
    • Longueil, Quebec, Canada, J4N 1L6
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H1T 2M4
      • Novartis Investigative Site
    • Sherbrooke, Quebec, Canada, J1J 2G2
      • Novartis Investigative Site
    • Ste-Foy, Quebec, Canada, G1V 4G2
      • Novartis Investigative Site
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7H 5M3
      • Novartis Investigative Site
• Denmark
  • Aalborg, Denmark, DK-9000
    • Novartis Investigative Site
  • Aalborg SV, Denmark, 9200
    • Novartis Investigative Site
  • Espergærde, Denmark, 3060
    • Novartis Investigative Site
  • Greve, Denmark, 2670
    • Novartis Investigative Site
  • Roslev, Denmark, 7870
    • Novartis Investigative Site
  • Vaerloese, Denmark, DK-3500
    • Novartis Investigative Site
  • Viborg, Denmark, 8800
    • Novartis Investigative Site
• Finland
  • Helsinki, Finland, 00180
    • Novartis Investigative Site
  • Helsinki, Finland, 00350
    • Novartis Investigative Site
  • Helsinki, Finland, 00810
    • Novartis Investigative Site
  • Kerava, Finland, 04200
    • Novartis Investigative Site
  • Oulu, Finland, 90100
    • Novartis Investigative Site
  • Tampere, Finland, 33100
    • Novartis Investigative Site
• France
  • Bourges, France, 18000
    • Novartis Investigative Site
  • La Chapelle sur Erdre, France, 44240
    • Novartis Investigative Site
  • La Roche sur Yon, France, 85000
    • Novartis Investigative Site
  • Le Pradet, France, 83220
    • Novartis Investigative Site
  • Murs Erigné, France, 49610
    • Novartis Investigative Site
  • Saint Avertin, France, 37550
    • Novartis Investigative Site
  • Tours, France, 37000
    • Novartis Investigative Site
  • Vihiers, France, 49310
    • Novartis Investigative Site
• Germany
  • Balve, Germany, 58802
    • Novartis Investigative Site
  • Beckingen, Germany, 66701
    • Novartis Investigative Site
  • Berlin, Germany, 13053
    • Novartis Investigative Site
  • Berlin, Germany, 10719
    • Novartis Investigative Site
  • Einbeck, Germany, 37574
    • Novartis Investigative Site
  • Erfurt, Germany, 99084
    • Novartis Investigative Site
  • Giengen, Germany, 89537
    • Novartis Investigative Site
  • Hagen, Germany, 58095
    • Novartis Investigative Site
  • Haigerloch, Germany, 72401
    • Novartis Investigative Site
  • Hamburg, Germany, 22335
    • Novartis Investigative Site
  • Kassel, Germany, 34125
    • Novartis Investigative Site
  • Krefeld, Germany, 47798
    • Novartis Investigative Site
  • Mahlberg, Germany, 77972
    • Novartis Investigative Site
  • Messkirch, Germany, 88605
    • Novartis Investigative Site
  • Reinfeld, Germany, 23858
    • Novartis Investigative Site
  • Siegen, Germany, 57074
    • Novartis Investigative Site
  • Wallerfing, Germany, 94574
    • Novartis Investigative Site
  • Warendorf, Germany, 48231
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1134
    • Novartis Investigative Site
  • Esztergom, Hungary, 2500
    • Novartis Investigative Site
  • Miskolc, Hungary, 3526
    • Novartis Investigative Site
  • Nyiregyháza, Hungary, 4400
    • Novartis Investigative Site
• Italy
  • CE
    • Caserta, CE, Italy, 81100
      • Novartis Investigative Site
  • FE
    • Cona, FE, Italy, 44100
      • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
  • IS
    • Pozzilli, IS, Italy, 86077
      • Novartis Investigative Site
  • MI
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
    • Vimercate, MI, Italy, 20059
      • Novartis Investigative Site
  • PA
    • Palermo, PA, Italy, 90127
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
  • PI
    • Pisa, PI, Italy, 56124
      • Novartis Investigative Site
    • Pisa, PI, Italy, 56126
      • Novartis Investigative Site
  • PV
    • Casorate Primo, PV, Italy, 27022
      • Novartis Investigative Site
    • Pavia, PV, Italy, 27100
      • Novartis Investigative Site
    • Stradella, PV, Italy, 27049
      • Novartis Investigative Site
  • SA
    • Mercato San Severino, SA, Italy, 84085
      • Novartis Investigative Site
  • SS
    • Sassari, SS, Italy, 07100
      • Novartis Investigative Site
  • UD
    • San Daniele Del Friuli, UD, Italy, 33038
      • Novartis Investigative Site
  • VV
    • Vibo Valentia, VV, Italy, 89900
      • Novartis Investigative Site
• Latvia
  • Daugavplis, Latvia, LV-5417
    • Novartis Investigative Site
  • Kuldiga, Latvia, LV-3300
    • Novartis Investigative Site
  • Ogre, Latvia, 5001
    • Novartis Investigative Site
  • Riga, Latvia, 1002
    • Novartis Investigative Site
  • Riga, Latvia, LV-1001
    • Novartis Investigative Site
  • Riga, Latvia, LV-1012
    • Novartis Investigative Site
• Lithuania
  • Alytus, Lithuania, LT-62381
    • Novartis Investigative Site
  • Kaunas, Lithuania, LT-47144
    • Novartis Investigative Site
  • Kaunas, Lithuania, LT-49387
    • Novartis Investigative Site
  • Kaunas, Lithuania, 3007
    • Novartis Investigative Site
  • Klaipeda, Lithuania, LT-92288
    • Novartis Investigative Site
• Netherlands
  • Den Bosch, Netherlands, 5216 GC
    • Novartis Investigative Site
  • Deurne, Netherlands, 5751 XJ
    • Novartis Investigative Site
  • Ermelo, Netherlands, 3851 EX
    • Novartis Investigative Site
  • Hoogwoud, Netherlands, 1718 BG
    • Novartis Investigative Site
  • Leeuwarden, Netherlands, 8934 AD
    • Novartis Investigative Site
  • Losser, Netherlands, 7581 BV
    • Novartis Investigative Site
  • Oude Pekela, Netherlands, 9665 AR
    • Novartis Investigative Site
  • Poortvliet, Netherlands, 4693 BT
    • Novartis Investigative Site
  • Wamel, Netherlands, 6659 BX
    • Novartis Investigative Site
• Poland
  • Olawa, Poland, 55-200
    • Novartis Investigative Site
  • Ostrow Wielkopolski, Poland, 63-400
    • Novartis Investigative Site
  • Tarnow, Poland, 33-100
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 121552
    • Novartis Investigative Site
  • Moscow, Russian Federation, 101990
    • Novartis Investigative Site
  • Moscow, Russian Federation, 105077
    • Novartis Investigative Site
  • S.-Petersburg, Russian Federation, 196247
    • Novartis Investigative Site
  • S.-Petersburg, Russian Federation, 191187
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 195067
    • Novartis Investigative Site
  • Saint-Petersburg, Russian Federation, 194044
    • Novartis Investigative Site
  • Saint-Petersburg, Russian Federation, 197341
    • Novartis Investigative Site
  • Sankt-Peterburg, Russian Federation, 197022
    • Novartis Investigative Site
• Slovakia
  • Dunajska Streda, Slovakia, 929 01
    • Novartis Investigative Site
  • Zilina, Slovakia, 012 07
    • Novartis Investigative Site
  • Slovak Republic
    • Banska Bystrica, Slovak Republic, Slovakia, 974 05
      • Novartis Investigative Site
    • Bratislava, Slovak Republic, Slovakia, 813 69
      • Novartis Investigative Site
    • Nitra, Slovak Republic, Slovakia, 949 01
      • Novartis Investigative Site
    • Presov, Slovak Republic, Slovakia, 080 01
      • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08820
    • Novartis Investigative Site
  • Hospitalet de Llbregat, Spain, 08902
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Petrel, Spain, 03610
    • Novartis Investigative Site
  • Riudecols, Spain, 43390
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41009
      • Novartis Investigative Site
  • Baleares
    • Palma de Mallorca, Baleares, Spain, 07007
      • Novartis Investigative Site
  • Cataluña
    • Badalona, Cataluña, Spain, 08914
      • Novartis Investigative Site
    • Barcelona, Cataluña, Spain, 08025
      • Novartis Investigative Site
    • Barcelona, Cataluña, Spain, 08905
      • Novartis Investigative Site
    • Tarrega, Cataluña, Spain, 25300
      • Novartis Investigative Site
    • Vic, Cataluña, Spain, 08500
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Alicante, Comunidad Valenciana, Spain, 03004
      • Novartis Investigative Site
    • Benidorm, Comunidad Valenciana, Spain, 03550
      • Novartis Investigative Site
    • Quart de Poblet, Comunidad Valenciana, Spain, 46930
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 460009
      • Novartis Investigative Site
  • Galicia
    • Begonte, Galicia, Spain, 27373
      • Novartis Investigative Site
    • Santiago de Compostela, Galicia, Spain, 15706
      • Novartis Investigative Site
• Sweden
  • Arvidsjaur, Sweden, 933 83
    • Novartis Investigative Site
  • Boden, Sweden, SE 961 31
    • Novartis Investigative Site
  • Karlstad, Sweden, 652 25
    • Novartis Investigative Site
  • Kil, Sweden, 665 30
    • Novartis Investigative Site
  • Kristianstad, Sweden, 291 54
    • Novartis Investigative Site
  • Lund, Sweden, SE-222 21
    • Novartis Investigative Site
  • Skellefteå, Sweden, SE 931 32
    • Novartis Investigative Site
• Taiwan
  • Changhua, Taiwan, 500
    • Novartis Investigative Site
  • Taichung County, Taiwan
    • Novartis Investigative Site
  • Taipei, Taiwan, 112
    • Novartis Investigative Site
  • Taipei, Taiwan, 114
    • Novartis Investigative Site
  • Taipei, Taiwan, 10449
    • Novartis Investigative Site
  • Taiwan ROC
    • Taichung, Taiwan ROC, Taiwan, 40201
      • Novartis Investigative Site
    • Tainan 704, Taiwan ROC, Taiwan
      • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-2041
      • Novartis Investigative Site
    • Muscle Shoals, Alabama, United States, 35662
      • Novartis Investigative Site
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Novartis Investigative Site
  • California
    • Buena Park, California, United States, 90620
      • Novartis Investigative Site
    • Fair Oaks, California, United States, 95628
      • Novartis Investigative Site
    • Long Beach, California, United States, 90806
      • Novartis Investigative Site
    • Los Angeles, California, United States, 90057
      • Novartis Investigative Site
    • Orangevale, California, United States, 95662
      • Novartis Investigative Site
    • Santa Ana, California, United States, 92701
      • Novartis Investigative Site
    • Stockton, California, United States, 95204
      • Novartis Investigative Site
    • Tustin, California, United States, 92780
      • Novartis Investigative Site
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Novartis Investigative Site
    • Pembroke Pines, Florida, United States, 33024
      • Novartis Investigative Site
    • Pembroke Pines, Florida, United States, 33029
      • Novartis Investigative Site
    • Pensacola, Florida, United States, 32504
      • Novartis Investigative Site
  • Georgia
    • Augusta, Georgia, United States, 30904
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60607
      • Novartis Investigative Site
    • Chicago, Illinois, United States, 60610
      • Novartis Investigative Site
    • Peoria, Illinois, United States, 61615
      • Novartis Investigative Site
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Novartis Investigative Site
    • Metairie, Louisiana, United States, 70006
      • Novartis Investigative Site
  • Michigan
    • Chelsea, Michigan, United States, 48118
      • Novartis Investigative Site
    • Royal Oak, Michigan, United States, 48073
      • Novartis Investigative Site
  • Minnesota
    • Brooklyn Center, Minnesota, United States, 55430-2168
      • Novartis Investigative Site
  • Missouri
    • St. Peters, Missouri, United States, 63376
      • Novartis Investigative Site
  • New Jersey
    • Toms River, New Jersey, United States, 08753
      • Novartis Investigative Site
    • Trenton, New Jersey, United States, 08629
      • Novartis Investigative Site
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Novartis Investigative Site
    • Cincinnati, Ohio, United States, 45224
      • Novartis Investigative Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73132-4904
      • Novartis Investigative Site
  • South Carolina
    • Simpsonville, South Carolina, United States, 29681
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75235
      • Novartis Investigative Site
    • Houston, Texas, United States, 77081
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030-3411
      • Novartis Investigative Site
    • Houston, Texas, United States, 77083
      • Novartis Investigative Site
    • Lake Jackson, Texas, United States, 77566
      • Novartis Investigative Site
  • Virginia
    • Richmond, Virginia, United States, 23294
      • Novartis Investigative Site
  • West Virginia
    • Charleston, West Virginia, United States, 25301
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or females from 18 up to and including 75 years
• Patients with mild-to-moderate uncomplicated essential hypertension, untreated or currently taking antihypertensive therapy (monotherapy or combination therapy of 2 drugs; therapy with a fixed dose combination of two active substances represents 2 drugs)
• Untreated patients must have had an office msDBP≥ 95 mmHg at the randomization visit (Visit 3) and the 2 preceding visits (Visits 1 and 2).
• Treated patients must have had an office msDBP≥ 90 mmHG after washout (Visit 2), and a msDBP> 95 mmHg at baseline (Visit 3);

Exclusion Criteria:

• Severe hypertension (msSBP ≥180 mmHg and/or msDBP ≥110 mmHg)
• History of angioedema, drug-related or otherwise, as reported by the patient
• Type 1 or Type 2 diabetes mellitus (according to the ADA criteria)
• History or evidence of a secondary form of hypertension, such as renal parenchymal hypertension, renovascular hypertension, coarctation of the aorta, primary hyperaldosteronism, Cushing's disease, drug-induced hypertension, unilateral or bilateral renal artery stenosis, pheochromocytoma, polycystic kidney disease, etc.
• History of angina pectoris, myocardial infarction, coronary bypass surgery, ischemic heart disease, surgical or percutaneous arterial intervention of any kind (coronary, carotid or peripheral intervention), stroke, TIA (transient ischemic attack), carotid artery stenosis, aortic aneurysm or peripheral arterial disease

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LCZ696 100 mg; Participants received LCZ696 100 mg and matching placebo to LCZ696, Valsartan and AHU377 (5 tablets and 2 capsules) daily.	Drug: Placebo; Drug: LCZ696
Experimental: LCZ696 200 mg; Participants received LCZ696 200 mg and matching placebo to LCZ696, Valsartan and AHU377 (5 tablets and 2 capsules) daily.	Drug: Placebo; Drug: LCZ696
Experimental: LCZ696 400 mg; Participants received LCZ696 400 mg (200 mg LCZ696 for one week and then up-titration to 400 mg LCZ696 for 7 weeks) and matching placebo to LCZ696, Valsartan and AHU377 (5 tablets and 2 capsules) daily.	Drug: Placebo; Drug: LCZ696
Active Comparator: Valsartan 80 mg; Participants received Valsartan 80 mg and matching placebo to LCZ696, Valsartan and AHU377 (5 tablets and 2 capsules) daily.	Drug: Placebo; Drug: Valsartan
Active Comparator: Valsartan 160 mg; Participants received Valsartan 160 mg and matching placebo to LCZ696, Valsatan and AHU377 (5 tablets and 2 capsules) daily.	Drug: Placebo; Drug: Valsartan
Active Comparator: Valsartan 320 mg; Participants received Valsartan 320 mg (160 mg valsartan capsules for one week followed by 320 mg valsartan capsules for 7 weeks) and matching placebo to LCZ696, Valsartan and AHU377 (5 tablets and 2 capsules) daily.	Drug: Placebo; Drug: Valsartan
Experimental: AHU377 200 mg; Participants received AHU377 200 mg and matching placebo to LCZ696 and Valsartan (5 tablets and 2 capsules) daily.	Drug: Placebo; Drug: AHU377
Placebo Comparator: Placebo; Participants received matching placebo to LCZ696, Valsartan and AHU377 (5 tablets and 2 capsules) daily.	Drug: Placebo

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, week 8

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.	baseline, week 8
Change From Baseline in 24-hour Mean Ambulatory DBP (maDBP) and maSBP	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.	baseline, 8 weeks
Change From Baseline in Daytime maDBP and maSBP	Hourly mean ambulatory DBP and SBP post-dosing was calculated for each post-dosing hour over 24 hours by taking the avergae 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.	baseline, 8 weeks
Change From Baseline in Nighttime maDBP and maSBP	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.	baseline, 8 weeks
Percentage 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
Percentage 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
Percentage of Participants Who Achieved Successful Control in msDBP	Successful control in msDBP is defined as msDBP <90 mmHg.	8 weeks
Percentage of Participants Who Achieved Successful Control in msSBP	Successful control in msSBP is defined as <140 mmHg.	8 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.
• Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010 Apr 10;375(9722):1255-66. doi: 10.1016/S0140-6736(09)61966-8. Epub 2010 Mar 16.

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): July 1, 2008
• Study Completion (Actual): July 1, 2008

Study Registration Dates

• First Submitted: October 5, 2007
• First Submitted That Met QC Criteria: October 25, 2007
• First Posted (Estimate): October 26, 2007

Study Record Updates

• Last Update Posted (Estimate): August 25, 2015
• Last Update Submitted That Met QC Criteria: August 11, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: Hypertension, valsartan, LCZ696
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696A2201