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

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

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.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: sacubitril/valsartan (LCZ696); Other: placebo to olmesartan; Drug: Amlodipine (Optional); Drug: olmesartan; Other: placebo to sacubitril/valsartan (LCZ696)

• Study Type: Interventional
• Enrollment (Actual): 115
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Novartis Investigative Site
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
• Switzerland
  • Basel, Switzerland, 4031
    • Novartis Investigative Site
• United Kingdom
  • Scotland
    • Glasgow, Scotland, United Kingdom, G12 8TA
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

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

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sacubitril/valsartan (LCZ696); 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); 200 mg tablets; Other: placebo to olmesartan; placebo; Drug: Amlodipine (Optional); If required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to treatment regimen
Active Comparator: olmesartan; 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: Amlodipine (Optional); If required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to treatment regimen; Drug: olmesartan; Other: placebo to sacubitril/valsartan (LCZ696); placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Hrabak-Paar M, Kircher A, Al Sayari S, Kopp S, Santini F, Schmieder RE, Kachenoura N, Yates D, Langenickel T, Bremerich J, Heye T. Variability of MRI Aortic Stiffness Measurements in a Multicenter Clinical Trial Setting: Intraobserver, Interobserver, and Intracenter Variability of Pulse Wave Velocity and Aortic Strain Measurement. Radiol Cardiothorac Imaging. 2020 Apr 30;2(2):e190090. doi: 10.1148/ryct.2020190090. eCollection 2020 Apr.
• Santini F, Pansini M, Hrabak-Paar M, Yates D, Langenickel TH, Bremerich J, Bieri O, Schubert T. On the optimal temporal resolution for phase contrast cardiovascular magnetic resonance imaging: establishment of baseline values. J Cardiovasc Magn Reson. 2020 Oct 5;22(1):72. doi: 10.1186/s12968-020-00669-1.

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: June 3, 2013
• First Submitted That Met QC Criteria: June 3, 2013
• First Posted (Estimate): June 6, 2013

Study Record Updates

• Last Update Posted (Actual): January 5, 2021
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Cardiovascular MRI; LCZ696,; Hypertension,; Aortic stiffness,; Central blood pressure,
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Amlodipine; Valsartan; Olmesartan; Olmesartan Medoxomil; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696A2224; 2012-005720-15 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No