A Study to Evaluate the Effect of LCZ696 on Aortic Stiffness in Subjects With Hypertension

Study Overview
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Brief Summary
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This was the first evaluation of the effects of LCZ696 on local and regional measures of aortic stiffness in subjects with mild to moderate hypertension and widened pulse pressure. The results of this exploratory study will help to understand the mechanism of action of LCZ696 and used to inform the design of future clinical studies with LCZ696 in subjects with cardiovascular diseases.

Official Title
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A Randomized, Double-blind, Active-controlled, Parallel Group, 52-week Study to Evaluate the Effect of LCZ696 Compared to Olmesartan on Regional Aortic Stiffness in Subjects With Essential Hypertension

Conditions
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Hypertension

Intervention / Treatment
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* Drug: sacubitril/valsartan (LCZ696)
* Drug: olmesartan
* Other: placebo to sacubitril/valsartan (LCZ696)
* Other: placebo to olmesartan
* Drug: Amlodipine (Optional)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Subjects with essential hypertension, untreated or currently taking antihypertensive therapy Key exclusion Criteria: women of child bearing potential (WOCBP) if not on highly effective contraception Malignant or severe hypertension (grade 3 of WHO classification) History or evidence of a secondary form of hypertension Transient ischemic cerebral attack (TIA) during the 12 months prior to screening or any history of stroke. Previous or current diagnosis of heart failure (New York Heart Association Class II-IV).

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sacubitril/valsartan (LCZ696)<br>Single drug treatment period: Patients received LCZ696 200mg once daily (q.d.) + placebo to 20 mg olmesartan q.d for 2 weeks. After 2 weeks, patients were dosed at the maintenance dose level (400 mg qd LCZ696 + placebo to 40 mg qd olmesartan) for 10 weeks. Add-on Period: After 12 weeks on single-drug treatment, patients continued in the study on the blinded maintenance dose and if required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to the treatment regimen and titrated according to the investigator's discretion to achieve target blood pressure. | Drug: sacubitril/valsartan (LCZ696)<br>* 200 mg tablets<br>Other: placebo to olmesartan<br>* placebo<br>Drug: Amlodipine (Optional)<br>* If required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to treatment regimen<br>|
| Active Comparator: olmesartan<br>Single drug treatment period: Patients received 20 mg olmesartan q.d + placebo to LCZ696 200mg once daily (q.d.) for 2 weeks. After 2 weeks, patients were dosed at the maintenance dose level (40 mg olmesartan q.d + placebo to 400 mg qd LCZ696) for 10 weeks. Add-on Period: After 12 weeks on single-drug treatment, patients continued in the study on the blinded maintenance dose and if required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to the treatment regimen and titrated according to the investigator's discretion to achieve target blood pressure. | Drug: olmesartan<br> <br> Other: placebo to sacubitril/valsartan (LCZ696)<br>* placebo<br>Drug: Amlodipine (Optional)<br>* If required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to treatment regimen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Ascending Aorta Distensibility at 52 Week | Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Ascending aorta distensibility was one of the 3 components for measuring local arota distensibility. | Baseline, 52 weeks | 
| Change From Baseline in Proximal Descending Aorta Distensibility at 52 Weeks | Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Proximal descending aorta distensibility was one of the 3 components for measuring local arota distensibility. | Baseline, 52 weeks | 
| Change From Baseline in Distal Descending Aorta Distensibility at 52 Weeks | Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic distensibility. Distal descending aorta distensibility was one of the 3 components for measuring local arota distensibility. | Baseline, 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Local Aortic Strain at 52 Weeks | Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of local aortic strain. Local aortic strain was measured by assessing ascending aorta strain, proximal descending aorta strain and distal descending aorta strain. | Baseline, 52 weeks | 
| Change From Baseline in Regional Aortic Pulse Wave Velocity at 52 Weeks | Cardiovascular magnetic resonance imaging (MRI) scans were obtained at baseline prior to randomization, at week 52 for the assessment of regional aortic pulse wave velocity. | Baseline, 52 weeks | 
| Change From Baseline in Central Blood Pressure at 52 Weeks | Central blood pressure was determined by measuring central systolic blood pressure , diastolic blood pressure and pulse pressure. | Baseline, 52 weeks | 
| Change From Baseline in Augmentation Pressure at 52 Weeks | Augmentation pressure is the added pressure during systole due to wave reflection. | Baseline, 52 weeks | 
| Change From Baseline in Augmentation Index at 52 Weeks | Augmentation index (Alx) is the percentage of the central pulse pressure due to wave reflection. | Baseline, 52 weeks | 
| Change From Baseline in Carotid-femoral Pulse Wave Velocity at 52 Weeks | For pulse wave velocity calculation, the pressure waveform at the femoral site (using a partially inflated custom blood pressure cuff) and the carotid site (using hand -held applanation tonometry) were measured simultaneously. Pulse wave analysis was performed on the central aortic pressure waveform as derived from the brachial pressure waveform recorded in a partially-inflated blood pressure cuff around the upper arm. | Baseline, 52 weeks | 
| Number of Patients With Reported Adverse Events, Serious Adverse Events and Death | This outcome measure summarizes patients with any adverse events, serious adverse events and death. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LCZ696,, Hypertension,, Aortic stiffness,, Central blood pressure,, Cardiovascular MRI