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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01870739
First received: June 3, 2013
Last updated: July 20, 2016
Last verified: July 2016
  Purpose
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 Intervention Phase
Hypertension
Drug: sacubitril/valsartan (LCZ696)
Drug: olmesartan
Other: placebo to sacubitril/valsartan (LCZ696)
Other: placebo to olmesartan
Drug: Amlodipine (Optional)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Change From Baseline in Ascending Aorta Distensibility at 52 Week [ Time Frame: Baseline, 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Proximal Descending Aorta Distensibility at 52 Weeks [ Time Frame: Baseline, 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Distal Descending Aorta Distensibility at 52 Weeks [ Time Frame: Baseline, 52 weeks ] [ Designated as safety issue: No ]
    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:
  • Change From Baseline in Local Aortic Strain at 52 Weeks [ Time Frame: Baseline, 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Regional Aortic Pulse Wave Velocity at 52 Weeks [ Time Frame: Baseline, 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Central Blood Pressure at 52 Weeks [ Time Frame: Baseline, 52 weeks ] [ Designated as safety issue: No ]
    Central blood pressure was determined by measuring central systolic blood pressure , diastolic blood pressure and pulse pressure.

  • Change From Baseline in Augmentation Pressure at 52 Weeks [ Time Frame: Baseline, 52 weeks ] [ Designated as safety issue: No ]
    Augmentation pressure is the added pressure during systole due to wave reflection.

  • Change From Baseline in Augmentation Index at 52 Weeks [ Time Frame: Baseline, 52 weeks ] [ Designated as safety issue: No ]
    Augmentation index (Alx) is the percentage of the central pulse pressure due to wave reflection.

  • Change From Baseline in Carotid-femoral Pulse Wave Velocity at 52 Weeks [ Time Frame: Baseline, 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Number of Patients With Reported Adverse Events, Serious Adverse Events and Death [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    This outcome measure summarizes patients with any adverse events, serious adverse events and death.


Enrollment: 115
Study Start Date: October 2013
Study Completion Date: June 2015
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
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
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: NCT01870739

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

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01870739     History of Changes
Other Study ID Numbers: CLCZ696A2224  2012-005720-15 
Study First Received: June 3, 2013
Results First Received: May 31, 2016
Last Updated: July 20, 2016
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Novartis:
LCZ696,
Hypertension,
Aortic stiffness,
Central blood pressure,
Cardiovascular MRI

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Olmesartan
Amlodipine
Valsartan
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

ClinicalTrials.gov processed this record on December 02, 2016