Evaluation of the Entresto Effect on Sympathic Nervous System in Patient With Heart Failure (B2AN-SNS)

Evaluation of the Effect of Double Inhibition of Angiotensin II AT1 Receptor and Neprilysin Activity on Sympathic Nervous System Activity in Patient With Heart Failure

The hyperactivation of the sympathetic nervous system is a feature of the heart failure and the determinants of disease progression and risk of sudden cardiac death. This research project aims to study, in the drug use conditions provided in the summary of product characteristics based on European marketing authorization (indications and dosage), the effect of the Entresto® on the activity of sympathic nervous system using the reference method, the microneurographic recording of sympathetic activity in muscle destiny (MSNA). This study will try to determine if the double inhibition of AT1 receptor and neprilysin activity result in lower sympathic nervous system burst rate versus single AT1 receptor inhibition using angiotensin-converting-enzyme inhibitor or AT1 receptor of angiotensin II inhibitor.

Study Overview

• Status: Terminated
• Conditions: Heart Failure
• Intervention / Treatment: Drug: valsartan/sacubitril 100 mg; Drug: valsartan/sacubitril 200 mg; Procedure: Microneurography

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Toulouse, France
    • CHU de Toulouse

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

Inclusion Criteria:

• Men or women with heart failure with symptomatic left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 40 %) with :

  • Functional class New York Heart Association II and at least 2 hospitalizations for cardiac decompensation in the year with N terminal pro brain-type natriuretic peptide ≥300 pg/ml (or brain-type natriuretic peptide ≥100 pg/ml) or usage of intravenous diuretics,
  • Functional class New York Heart Association III-IV,
  • Insufficiently controlled by alternative drug-free therapies (surgery, cardiac resynchronization ...) or well managed drug therapies: angiotensin-converting-enzyme inhibitor, AT1 receptor of angiotensin II inhibitor diuretics or beta blockers.
  • Treated by maximum dosage of AT1 receptor of angiotensin II inhibitor or angiotensin-converting-enzyme inhibitor for New York Heart Association II patient or 50% of the recommended dose for New York Heart Association III-IV patients or New York Heart Association II patients with clinical manifestation restricting the use of maximum dosage, like orthostatic hypotension.
• Patient member of his home social security scheme

Exclusion Criteria:

• Patient who are receiving direct renin inhibitor like aliskiren
• Patient who are receiving phosphodiesterase V inhibitors
• Patient who are receiving a potassium-sparing drug
• Patient with medical history of angioedema with previous treatment by angiotensin-converting-enzyme inhibitor or AT1 receptor of angiotensin II inhibitor
• Hypersensitivity to any component of Entresto®
• Adult protected by the law
• Severe renal impairment (DFGe <30 ml/min/1,73 m2)
• Severe hepatic impairment, cirrhosis or cholestasis (Child-Pugh C class)
• Patient with are receiving anticoagulant therapies or suffering from known hemostatic trouble
• Patient participating in another biomedical research or with an active exclusion period
• Pregnancy
• Breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Entresto; Stop of all angiotensin-converting-enzyme inhibitor or antagonist of angiotensin II receptor during 2 days.; valsartan/sacubitril 100 mg tablets (51 and 49 mg) during 2 to 4 weeks twice a day.; valsartan/sacubitril 200 mg tablets (103 and 97 mg) during 2 to 4 weeks twice a day.; Microneurography recording of sympathetic activity in muscle destiny (MSNA)	Drug: valsartan/sacubitril 100 mg; Treatment with 100 mg tablets during 2 to 4 weeks; Other Names: Entresto 100 mg; Drug: valsartan/sacubitril 200 mg; Treatment with 200 mg tablets during 2 to 4 weeks; Other Names: Entresto 200 mg; Procedure: Microneurography; Microneurography recording of sympathetic nervous system activity in muscle destiny; Other Names: MSNA
PLACEBO_COMPARATOR: Control; Hearth failure treatment as usual (angiotensin-converting-enzyme inhibitor or antagonist of angiotensin II receptor); Microneurography recording of sympathetic activity in muscle destiny (MSNA) will be done	Procedure: Microneurography; Microneurography recording of sympathetic nervous system activity in muscle destiny; Other Names: MSNA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of sympathetic nervous system activity as assessed by microneurography recording recording of sympathetic activity in muscle destiny	Evaluation of sympathetic nervous system activity in burst/minute	Up to 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of severity of heart failure	assessed by New York Heart Association stage	Day 0
Evaluation of severity of heart failure	assessed by New York Heart Association stage	Day 2
Evaluation of severity of heart failure	assessed by New York Heart Association stage	Up to 4 weeks
Evaluation of severity of heart failure	assessed by New York Heart Association stage	Up to 8 weeks
Comparison of treatment effect on pro-brain natriuretic peptide serum levels at baseline and at the end of treatment period	pro-brain natriuretic peptide serum levels	Day 0 and up to 8 weeks

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Michel Galinier, MD, CHU Toulouse

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2016
• Primary Completion (ACTUAL): January 1, 2018
• Study Completion (ACTUAL): January 1, 2018

Study Registration Dates

• First Submitted: May 26, 2016
• First Submitted That Met QC Criteria: May 26, 2016
• First Posted (ESTIMATE): June 1, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 7, 2019
• Last Update Submitted That Met QC Criteria: February 5, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Nervous System; Cardiac disease
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: RC31/15/7746

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED