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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01692301
First received: September 20, 2012
Last updated: March 31, 2016
Last verified: March 2016
  Purpose
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 Intervention Phase
Hypertension
Drug: LCZ696
Drug: Olmesartan
Drug: LCZ696 matching placebo
Drug: Olmesartan matching placebo
Drug: amlodipine
Drug: hydrochlorothiazide
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 12 Weeks [ Time Frame: baseline, 12 weeks ] [ Designated as safety issue: No ]

    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:
  • Change From Baseline in Mean Central Pulse (CPP) Pressure [ Time Frame: Baseline, 12 weeks, and 52 weeks ] [ Designated as safety issue: No ]
  • Change From Baseline in Mean Pulse Wave Velocity (PWV) [ Time Frame: baseline, 12 weeks, and 52 weeks ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 52 Weeks [ Time Frame: baseline, 52 weeks ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) [ Time Frame: baseline, 12 weeks, and 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) [ Time Frame: baseline, 12 weeks, and 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean Sitting Pulse Pressure (msPP) [ Time Frame: baseline, 12 weeks, and 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean Arterial Pressure (MAP) [ Time Frame: baseline, 12 weeks, and 52 weeks ] [ Designated as safety issue: No ]
    Mean arterial pressure (MAP) was calculated from mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) as (2 * msDBP + msSBP)/3.

  • Change From Baseline in Mean 24-hour Systolic Blood Pressure (maSBP) [ Time Frame: Baseline, 12 weeks, and 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean 24-hour Diastolic Blood Pressure (maDBP) [ Time Frame: Baseline, 12 weeks, and 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (maPP) [ Time Frame: Baseline, 12 weeks, and 52 weeks ] [ Designated as safety issue: No ]
    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.


Enrollment: 454
Study Start Date: December 2012
Study Completion Date: April 2015
Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   60 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01692301

  Show 47 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01692301     History of Changes
Other Study ID Numbers: CLCZ696A2216  2012-002899-14 
Study First Received: September 20, 2012
Results First Received: March 31, 2016
Last Updated: March 31, 2016
Health Authority: United States: Food and Drug Administration
Argentina: Ministry of Health
Brazil: Ministry of Health
Colombia: National Institutes of Health
France: Ministry of Health
Germany: Ministry of Health
Greece: Ministry of Health and Welfare
Italy: Ministry of Health
Japan: Ministry of Health, Labor and Welfare
Korea: Food and Drug Administration
Russia: Pharmacological Committee, Ministry of Health
Spain: Ministry of Health
Taiwan: Department of Health

Keywords provided by Novartis:
hypertension, elderly, central aortic pulse pressure, central pulse pressure, pulse wave velocity

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Olmesartan
Amlodipine
Valsartan
Hydrochlorothiazide
Olmesartan Medoxomil
LCZ 696
Antihypertensive Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors

ClinicalTrials.gov processed this record on December 02, 2016