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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Hypertension

Intervention / Treatment
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* Drug: LCZ696
* Drug: Olmesartan
* Drug: LCZ696 matching placebo
* Drug: Olmesartan matching placebo
* Drug: amlodipine
* Drug: hydrochlorothiazide


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female patients ≥ 60 years of age. Patients with essential hypertension, untreated or currently taking antihypertensive therapy. 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. 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. All patients must have pulse pressure >60 mmHg at Visit 201. Pulse pressure is defined as msSBP- msDBP. 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: Malignant or severe hypertension (grade 3 of WHO classification; msDBP ≥110 mmHg and/or msSBP ≥ 180 mmHg) History of angioedema, drug-related or otherwise. 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. Transient ischemic cerebral attack (TIA) during the 12 months prior to Visit 1 or any history of stroke. History of myocardial infarction, coronary bypass surgery or any percutaneous coronary intervention (PCI) during the 12 months prior to Visit 1. 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.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCZ696 (sacubitril/valsartan)<br>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<br>* 200 mg tablet<br>* Other names: sacubitril/valsartan;Drug: LCZ696 matching placebo<br>* LCZ696 Matching Placebo tablet<br>Drug: Olmesartan matching placebo<br>* Olmesartan matching placebo capsule<br>Drug: amlodipine<br>* amlodipine 2.5 mg or 5 mg tablets<br>Drug: hydrochlorothiazide<br>* hydrochlorothiazide 6.25mg, 12.5mg, or 25 mg tablets<br>|
| Active Comparator: Olmesartan<br>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<br>* 20 mg and 40 mg capsules<br>Drug: LCZ696 matching placebo<br>* LCZ696 Matching Placebo tablet<br>Drug: amlodipine<br>* amlodipine 2.5 mg or 5 mg tablets<br>Drug: hydrochlorothiazide<br>* hydrochlorothiazide 6.25mg, 12.5mg, or 25 mg tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 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. | baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Central Pulse (CPP) Pressure |  | Baseline, 12 weeks, and 52 weeks | 
| Change From Baseline in Mean Pulse Wave Velocity (PWV) | 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. | baseline, 12 weeks, and 52 weeks | 
| Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 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. | baseline, 52 weeks | 
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | 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. | baseline, 12 weeks, and 52 weeks | 
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | 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. | baseline, 12 weeks, and 52 weeks | 
| Change From Baseline in Mean Sitting Pulse Pressure (msPP) | 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. | baseline, 12 weeks, and 52 weeks | 
| Change From Baseline in Mean Arterial Pressure (MAP) | Mean arterial pressure (MAP) was calculated from mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) as (2 * msDBP + msSBP)/3. | baseline, 12 weeks, and 52 weeks | 
| Change From Baseline in Mean 24-hour Systolic Blood Pressure (maSBP) | 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. | Baseline, 12 weeks, and 52 weeks | 
| Change From Baseline in Mean 24-hour Diastolic Blood Pressure (maDBP) | 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. | Baseline, 12 weeks, and 52 weeks | 
| Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (maPP) | 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. | Baseline, 12 weeks, and 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypertension, elderly, central aortic pulse pressure, central pulse pressure, pulse wave velocity