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

• ClinicalTrials.gov Identifier: NCT01870739
• Recruitment Status: Completed
• First Posted: June 6, 2013
• Results First Posted: September 1, 2016
• Last Update Posted: January 5, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hypertension	Drug: sacubitril/valsartan (LCZ696); Drug: olmesartan; Other: placebo to sacubitril/valsartan (LCZ696); Other: placebo to olmesartan; Drug: Amlodipine (Optional)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 115 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: October 2013
• Actual Primary Completion Date: June 2015
• Actual Study Completion Date: June 2015

Arms and Interventions

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: olmesartan; Other: placebo to sacubitril/valsartan (LCZ696); placebo; Drug: Amlodipine (Optional); If required, open label amlodipine (2.5 mg, 5 mg, or 10 mg qd) was added to treatment regimen

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Ascending Aorta Distensibility at 52 Week [ Time Frame: Baseline, 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. Ascending aorta distensibility was one of the 3 components for measuring local arota distensibility.
2. Change From Baseline in Proximal Descending Aorta Distensibility at 52 Weeks [ Time Frame: Baseline, 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.
3. Change From Baseline in Distal Descending Aorta Distensibility at 52 Weeks [ Time Frame: Baseline, 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.

Secondary Outcome Measures :

1. Change From Baseline in Local Aortic Strain at 52 Weeks [ Time Frame: Baseline, 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.
2. Change From Baseline in Regional Aortic Pulse Wave Velocity at 52 Weeks [ Time Frame: Baseline, 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.
3. Change From Baseline in Central Blood Pressure at 52 Weeks [ Time Frame: Baseline, 52 weeks ]
   Central blood pressure was determined by measuring central systolic blood pressure , diastolic blood pressure and pulse pressure.
4. Change From Baseline in Augmentation Pressure at 52 Weeks [ Time Frame: Baseline, 52 weeks ]
   Augmentation pressure is the added pressure during systole due to wave reflection.
5. Change From Baseline in Augmentation Index at 52 Weeks [ Time Frame: Baseline, 52 weeks ]
   Augmentation index (Alx) is the percentage of the central pulse pressure due to wave reflection.
6. Change From Baseline in Carotid-femoral Pulse Wave Velocity at 52 Weeks [ Time Frame: Baseline, 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.
7. Number of Patients With Reported Adverse Events, Serious Adverse Events and Death [ Time Frame: 12 weeks ]
   This outcome measure summarizes patients with any adverse events, serious adverse events and death.

Eligibility Criteria

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

Criteria

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).

Contacts and Locations

Locations

Germany

Novartis Investigative Site

Berlin, Germany, 10117

Novartis Investigative Site

Erlangen, Germany, 91054

Switzerland

Novartis Investigative Site

Basel, Switzerland, 4031

United Kingdom

Novartis Investigative Site

Glasgow, Scotland, United Kingdom, G12 8TA

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Additional Information:

A Plain Language Trial Summary is available on novartisclinicaltrials.com 

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

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.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01870739
• Other Study ID Numbers: CLCZ696A2224; 2012-005720-15 ( EudraCT Number )
• First Posted: June 6, 2013
• Results First Posted: September 1, 2016
• Last Update Posted: January 5, 2021
• Last Verified: March 2019

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

LCZ696,; Hypertension,; Aortic stiffness,; Central blood pressure,; Cardiovascular MRI

Additional relevant MeSH terms:

Sacubitril and valsartan sodium hydrate drug combination; Hypertension; Vascular Diseases; Cardiovascular Diseases; Amlodipine; Valsartan; 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