Study of the Safety and Efficacy of LCZ696 on Arterial Stiffness in Elderly Patients With Hypertension

• ClinicalTrials.gov Identifier: NCT01692301
• Recruitment Status: Completed
• First Posted: September 25, 2012
• Results First Posted: May 4, 2016
• Last Update Posted: May 4, 2016
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

The study examined the efficacy of LCZ696 in comparison to the ARB olmesartan on Central Aortic Systolic Blood Pressure (CASP) and other measures of central hemodynamics and arterial stiffness in elderly patients with an elevated systolic blood pressure (SBP) and widened pulse pressure (PP).

Condition or disease	Intervention/treatment	Phase
Hypertension	Drug: LCZ696; Drug: Olmesartan; Drug: LCZ696 matching placebo; Drug: Olmesartan matching placebo; Drug: amlodipine; Drug: hydrochlorothiazide	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 454 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind 52-week Study to Evaluate the Safety and Efficacy of an LCZ696 Regimen Compared to an Olmesartan Regimen on Arterial Stiffness Through Assessment of Central Blood Pressure in Elderly Patients With Hypertension
• Study Start Date: December 2012
• Actual Primary Completion Date: April 2015
• Actual Study Completion Date: April 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: LCZ696 (sacubitril/valsartan); Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.	Drug: LCZ696; 200 mg tablet; Other Name: sacubitril/valsartan; Drug: LCZ696 matching placebo; LCZ696 Matching Placebo tablet; Drug: Olmesartan matching placebo; Olmesartan matching placebo capsule; Drug: amlodipine; amlodipine 2.5 mg or 5 mg tablets; Drug: hydrochlorothiazide; hydrochlorothiazide 6.25mg, 12.5mg, or 25 mg tablets
Active Comparator: Olmesartan; Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.	Drug: Olmesartan; 20 mg and 40 mg capsules; Drug: LCZ696 matching placebo; LCZ696 Matching Placebo tablet; Drug: amlodipine; amlodipine 2.5 mg or 5 mg tablets; Drug: hydrochlorothiazide; hydrochlorothiazide 6.25mg, 12.5mg, or 25 mg tablets

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 12 Weeks [ Time Frame: baseline, 12 weeks ]

   Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software.

   At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.

Secondary Outcome Measures :

1. Change From Baseline in Mean Central Pulse (CPP) Pressure [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
2. Change From Baseline in Mean Pulse Wave Velocity (PWV) [ Time Frame: baseline, 12 weeks, and 52 weeks ]

   Pulse wave velocity recordings were performed on patient while in a supine, face-up position.

   Tonometry was performed on the carotid simultaneously with the cuff inflation over the femoral artery. Two pulse wave velocity measures, meeting all quality control criteria were captured at baseline, week 12 and week 52.

3. Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 52 Weeks [ Time Frame: baseline, 52 weeks ]

   Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software.

   At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.

4. Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) [ Time Frame: baseline, 12 weeks, and 52 weeks ]
   At the first study visit, the patient had his/her blood pressure (BP) measured in both arms; the arm in which the highest sitting SBP was found was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for 5 minutes, SBP were measured 3 times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1- to 2-minute intervals and the mean of those 3 measurements was used as the average sitting office BP for that visit.
5. Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) [ Time Frame: baseline, 12 weeks, and 52 weeks ]
   At the first study visit, the patient had his/her blood pressure (BP) measured in both arms; the arm in which the highest sitting SBP was found was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for 5 minutes, DBP were measured 3 times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1- to 2-minute intervals and the mean of those 3 measurements was used as the average sitting office BP for that visit.
6. Change From Baseline in Mean Sitting Pulse Pressure (msPP) [ Time Frame: baseline, 12 weeks, and 52 weeks ]
   Mean sitting pulse pressure for each patient and visit was calculated as the difference between the calculated values of mean sitting systolic blood pressure and mean sitting diastolic blood pressure.
7. Change From Baseline in Mean Arterial Pressure (MAP) [ Time Frame: baseline, 12 weeks, and 52 weeks ]
   Mean arterial pressure (MAP) was calculated from mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) as (2 * msDBP + msSBP)/3.
8. Change From Baseline in Mean 24-hour Systolic Blood Pressure (maSBP) [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
   An Ambulatory Blood Pressure Monitor (ABPM) measured a participant's blood pressure over a 24 hour period using an automated validated monitoring device at baseline, week 12 and at week 52 starting one day before each visit. The 24 hour maSBP was calculated by taking the mean of all ambulatory systolic blood pressure readings for the 24 hour period.
9. Change From Baseline in Mean 24-hour Diastolic Blood Pressure (maDBP) [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
   An Ambulatory Blood Pressure Monitor (ABPM) measured a participant's blood pressure over a 24 hour period using an automated validated monitoring device at baseline, week 12 and at week 52 starting one day before each visit. The 24 hour maDBP was calculated by taking the mean of all ambulatory systolic blood pressure readings for the 24 hour period.
10. Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (maPP) [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
    Mean 24 hour ambulatory pulse pressure was calculated as the difference between the mean 24 hour systolic and diastolic ambulatory blood pressure in corresponding visits i.e. baseline, week 12 and week 52.

Eligibility Criteria

• Ages Eligible for Study: 60 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

1. Male and female patients ≥ 60 years of age.
2. Patients with essential hypertension, untreated or currently taking antihypertensive therapy.
3. Untreated patients must have an office msSBP ≥150 mmHg and <180 mmHg at Visit 101 and Visit 201 if they are newly diagnosed or have not been treated with antihypertensive drugs for the 4 weeks prior to Visit 1.
4. Treated patients must have an office msSBP ≥140 mmHg and <180 mmHg at Visit 102 (or Visit 103) and msSBP ≥150 mmHg and <180 mmHg at Visit 201 if they have been treated with antihypertensive drugs for the 4 weeks prior to Visit 1.
5. All patients must have pulse pressure >60 mmHg at Visit 201. Pulse pressure is defined as msSBP- msDBP.
6. Patients must have a difference in msSBP within +/-15 mmHg between Visit 201 (randomization) and the visit immediately prior to Visit 201.

Key Exclusion Criteria:

1. Malignant or severe hypertension (grade 3 of WHO classification; msDBP ≥110 mmHg and/or msSBP ≥ 180 mmHg)
2. History of angioedema, drug-related or otherwise.
3. History or evidence of a secondary form of hypertension, including but not limited to any of the following: renal parenchymal hypertension, renovascular hypertension (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing's disease, pheochromocytoma, polycystic kidney disease, and drug-induced hypertension.
4. Transient ischemic cerebral attack (TIA) during the 12 months prior to Visit 1 or any history of stroke.
5. History of myocardial infarction, coronary bypass surgery or any percutaneous coronary intervention (PCI) during the 12 months prior to Visit 1.
6. History of atrial fibrillation or atrial flutter during the 3 months prior to Visit 1, or active atrial fibrillation or atrial flutter on the ECG at screening.

Contacts and Locations

Locations

United States, Florida

Novartis Investigative Site

Clearwater, Florida, United States, 33756

United States, Illinois

Novartis Investigative Site

Chicago, Illinois, United States, 60607

United States, Maryland

Novartis Investigative Site

Baltimore, Maryland, United States, 21204

United States, Mississippi

Novartis Investigative Site

Belzoni, Mississippi, United States, 39038

Novartis Investigative Site

Jackson, Mississippi, United States, 39209

United States, Missouri

Novartis Investigative Site

St. Louis, Missouri, United States, 63141

United States, New York

Novartis Investigative Site

Buffalo, New York, United States, 14215

United States, Ohio

Novartis Investigative Site

Cincinnati, Ohio, United States, 45224

United States, Texas

Novartis Investigative Site

Houston, Texas, United States, 77081

Novartis Investigative Site

Lake Jackson, Texas, United States, 77566

Novartis Investigative Site

Pasadena, Texas, United States, 77504

Argentina

Novartis Investigative Site

Caba, Buenos Aires, Argentina, C1440AAD

Novartis Investigative Site

Ramos Mejia, Buenos Aires, Argentina, B1704ETD

Novartis Investigative Site

Rosario, Santa Fe, Argentina, S2000CXH

Colombia

Novartis Investigative Site

Barranquilla, Atlantico, Colombia

Novartis Investigative Site

Barranquilla, Colombia

France

Novartis Investigative Site

Paris, France, 75015

Germany

Novartis Investigative Site

Berlin, Germany, 10117

Novartis Investigative Site

Nuernberg, Germany, 90471

Greece

Novartis Investigative Site

Athens, Greece, 11525

Novartis Investigative Site

Athens, Greece, 11526

Novartis Investigative Site

Thessaloniki, Greece, 54642

Italy

Novartis Investigative Site

Treviglio, BG, Italy, 24047

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Pisa, PI, Italy, 56126

Novartis Investigative Site

San Daniele Del Friuli, UD, Italy, 33038

Japan

Novartis Investigative Site

Shimotsuke-city, Tochigi, Japan, 329-0498

Korea, Republic of

Novartis Investigative Site

Bucheon, Gyeonggi-do, Korea, Republic of, 424-717

Novartis Investigative Site

Seoul, Korea, Korea, Republic of, 110 744

Russian Federation

Novartis Investigative Site

Moscow, Russian Federation, 101990

Novartis Investigative Site

Moscow, Russian Federation, 117198

Novartis Investigative Site

Moscow, Russian Federation, 119992

Novartis Investigative Site

Saint Petersburg, Russian Federation, 197022

Novartis Investigative Site

Saint-Petersburg, Russian Federation, 197341

Novartis Investigative Site

Yaroslavl, Russian Federation, 150047

Spain

Novartis Investigative Site

Sevilla, Andalucia, Spain, 41071

Novartis Investigative Site

Jerez de La Frontera, Cadiz, Spain, 11407

Novartis Investigative Site

Barcelona, Cataluna, Spain, 08003

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08025

Novartis Investigative Site

Terrassa, Catalunya, Spain, 08221

Novartis Investigative Site

Centelles, Cataluña, Spain, 08540

Novartis Investigative Site

Puerto de Sagunto, Comunidad Valenciana, Spain, 46520

Novartis Investigative Site

La Coruna, Galicia, Spain, 15706

Novartis Investigative Site

Madrid, Spain, 28034

Novartis Investigative Site

Madrid, Spain, 28041

Taiwan

Novartis Investigative Site

Taipei, Taiwan, ROC, Taiwan, 112

Novartis Investigative Site

Taichung, Taiwan, 40447

Novartis Investigative Site

Taipei, Taiwan, 114

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Williams B, Cockcroft JR, Kario K, Zappe DH, Cardenas P, Hester A, Brunel P, Zhang J. Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study. BMJ Open. 2014 Feb 4;4(2):e004254. doi: 10.1136/bmjopen-2013-004254.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01692301
• Other Study ID Numbers: CLCZ696A2216; 2012-002899-14 ( EudraCT Number )
• First Posted: September 25, 2012
• Results First Posted: May 4, 2016
• Last Update Posted: May 4, 2016
• Last Verified: March 2016

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

hypertension, elderly, central aortic pulse pressure, central pulse pressure, pulse wave velocity

Additional relevant MeSH terms:

Sacubitril and valsartan sodium hydrate drug combination; Hypertension; Vascular Diseases; Cardiovascular Diseases; Amlodipine; Valsartan; Hydrochlorothiazide; Olmesartan; Olmesartan Medoxomil; Antihypertensive Agents; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Vasodilator Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Diuretics; Natriuretic Agents; Sodium Chloride Symporter Inhibitors