Influences of Angiotensin-neprilysin Inhibition on Sympathetic Activity in Heart Failure

NCT03415906 | Withdrawn Phase 2 DMC

• 1 other identifier: M17-05-LCZ-ARNI
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The autonomic nervous system plays an important role in controlling the circulation. Increased sympathetic activity has detrimental effects in patients with heart failure. The purpose of this study is to test the hypothesis that combined angiotensin receptor + neprilysin inhibition results in lower sympathetic activity than angiotensin receptor inhibition alone.

Conditions

Heart Failure

Keywords

angiotensin receptor blocker; neprilysin inhibition; sympathetic activity; baroreflex; microneurography; functional MRI

Outcome Measures

Primary Outcomes (1)

• MSNA burst frequency [bursts/min]

  Bursts of vasoconstrictor sympathetic nerve activity directed to skeletal muscle (muscle sympathetic nerve activity, MSNA) per minute

  For 5 minutes at the end of both treatments

Secondary Outcomes (9)

• DBP [mmHg]

  For 5 minutes at the end of both treatments

• PVN activity [unitless]

  For 20 minutes at the end of both treatments

• NTS activity [unitless]

  For 20 minutes at the end of both treatments

• MSNA burst incidence [bursts/100 heartbeats]

  For 5 minutes at the end of both treatments

• MSNA burst area [au/min]

  For 5 minutes at the end of both treatments

Other Outcomes (6)

• GLS [%]

  For 10 seconds at the end of both treatments

• E/E' [ratio]

  For 10 seconds at the end of both treatments

• sPAP [mmHg]

  For 10 seconds at the end of both treatments

Study Arms (2)

sacubitril+valsartan

EXPERIMENTAL

Combined angiotensin receptor and neprilysin inhibition

Combination Product: sacubitril+valsartan

valsartan

ACTIVE COMPARATOR

Angiotensin receptor inhibition alone

Drug: valsartan

Interventions

sacubitril+valsartan COMBINATION_PRODUCT

Combined angiotensin receptor + neprilysin inhibition

sacubitril+valsartan

valsartan DRUG

Angiotensin receptor inhibition alone

Also known as: Angiotensin receptor blocker (AT1-receptor blocker)

valsartan

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women or men at the age ≥ 18 years, ≤ 80 years and able to give written informed consent
• Heart failure NYHA class II-III
• Ejection fraction of 40 % or less
• Stable dose of an ACE inhibitor or ARB over the last 4 weeks (A 2-day ACE inhibitor washout is scheduled before run-in; see Figure 3 on page 29.)
• Stable dose of a beta-blocker over the last 4 weeks unless contraindicated or not tolerated
• Patient has to be in sinus rhythm
• Patients capable of understanding the investigational nature, potential risks and benefits of the clinical trial
• Women without childbearing potential defined by:
• at least 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral oophorectomy or
• hysterectomy or uterine agenesis or
• ≥ 50 years and in postmenopausal state ≥ 1 year or
• \< 50 years and in postmenopausal state ≥ 1 year with urine FSH \> 40 IU/l and urine estrogen \< 30 ng/l or a negative estrogen test OR
• Women of childbearing potential with a negative urine ß-HCG pregnancy test at screening who agree to meet one of the following criteria from the time of screening, during the study and for a period of 7 days following the last administration of study medication:
• correct use of at least an acceptable effective contraceptive measure. The following are deemed acceptable in this study: hormonal contraceptives (combined oral contraceptives and estrogen-free pills with desogestrel, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release), intrauterine device (IUS))
• true abstinence (periodic abstinence and withdrawal are not acceptable methods of contraception)

You may not qualify if:

• History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACE inhibitors (ACE-Is), ARBs, or neprilysin inhibitors, as well as known or suspected contraindications to the study drugs
• History of angioedema
• Recent acute decompensated heart failure within 2 months before screening
• Symptomatic hypotension and/or office systolic BP \<110 mmHg at screening measured according to the recommendations of the European Society of Hypertension
• Combined intake of an ACE inhibitor and ARB over the last 4 weeks
• Estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m²
• Concomitant medication with Aliskiren in patients with Diabetes or patients with eGFR \< 60 mL/min/1.73 m²
• Serum potassium \>5.2 mmol/L at Visit 1 (screening)
• Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid, or other major cardiovascular surgery, PCI, or carotid angioplasty within the 3 months before screening
• History of heart transplant or on a transplant list or with LV assistance device
• History of severe pulmonary disease
• Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1
• Presence of hemodynamically significant mitral and/or aortic valve disease/ left ventricular outflow tract obstruction, except mitral regurgitation secondary to LV dilatation
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs
• Evidence of hepatic disease as determined by any one of the following: aspartate aminotransferase or alanine aminotransferase values exceeding 2× upper limit of normal at Visit 1, history of hepatic encephalopathy, history of esophageal varices, or history of porto-caval shunt

Sponsors & Collaborators

• Hannover Medical School: lead
• DLR German Aerospace Center: collaborator

Study Sites (1)

Clinical Research Center Hannover, Hannover Medical School

Hanover, 30625, Germany

Location

MeSH Terms

Conditions

Heart Failure

Interventions

sacubitril and valsartan sodium hydrate drug combination; Valsartan; Angiotensin Receptor Antagonists

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: double
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, monocentric, active-controlled, double-blind, cross-over with randomized sequence of treatments

Study Record Dates

• First Submitted: January 2, 2018
• First Posted: January 30, 2018
• Study Start: December 14, 2017
• Primary Completion: September 6, 2018
• Study Completion: September 6, 2018
• Last Updated: October 9, 2018

Record last verified: 2018-10

Locations

DE (1)