- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03415906
Influences of Angiotensin-neprilysin Inhibition on Sympathetic Activity in Heart Failure (ARNI-Sy)
Influences of Angiotensin-neprilysin Inhibition With Sacubitril/Valsartan (ENTRESTO®) on Centrally Generated Sympathetic Activity in Heart Failure Patients
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.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Phase
- Phase 2
Contacts and Locations
Study Locations
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Hannover, Germany, 30625
- Clinical Research Center Hannover, Hannover Medical School
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- 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)
- sexual relationship only with female partners and/or sterile male partners OR Male
- Signed written informed consent and willingness to comply with treatment and follow- up procedures.
Exclusion Criteria:
- 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
- Contraindications precluding microneurography measurements, such as relevant peripheral neuropathy as judged by the investigator
- Pregnancy or lactation period
- Current participation in any other clinical trial or participation in another clinical trial within 30 days before screening
- Known or suspected hypersensitivity to any of the active substances or any excipients of the investigational medicinal products
- Vulnerable subjects (i.e. persons under any administrative or legal supervision or persons kept in detention)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: sacubitril+valsartan
Combined angiotensin receptor and neprilysin inhibition
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Combined angiotensin receptor + neprilysin inhibition
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Active Comparator: valsartan
Angiotensin receptor inhibition alone
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Angiotensin receptor inhibition alone
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
MSNA burst frequency [bursts/min]
Time Frame: For 5 minutes at the end of both treatments
|
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
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
DBP [mmHg]
Time Frame: For 5 minutes at the end of both treatments
|
Diastolic blood pressure
|
For 5 minutes at the end of both treatments
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PVN activity [unitless]
Time Frame: For 20 minutes at the end of both treatments
|
Using functional Magnetic Resonance Imaging (fMRI) with concurrent Lower Body Negative Pressure (LBNP), we will identify the paraventricular hypothalamic nucleus (PVN) by its activity change from low to high LBNP stimulation in a 20-minute paradigm.
Activity will be reported as a z-scores (no unit) averaged over the entire activation cluster.
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For 20 minutes at the end of both treatments
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NTS activity [unitless]
Time Frame: For 20 minutes at the end of both treatments
|
Using functional Magnetic Resonance Imaging (fMRI) with concurrent Lower Body Negative Pressure (LBNP), we will identify the nucleus of the solitary tract (NTS) by its activity change from low to high LBNP stimulation in a 20-minute paradigm.
Activity will be reported as a z-scores (no unit) averaged over the entire activation cluster.
|
For 20 minutes at the end of both treatments
|
MSNA burst incidence [bursts/100 heartbeats]
Time Frame: For 5 minutes at the end of both treatments
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Bursts of vasoconstrictor sympathetic nerve activity normalized to heart rate
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For 5 minutes at the end of both treatments
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MSNA burst area [au/min]
Time Frame: For 5 minutes at the end of both treatments
|
Area under the bursts in the integrated neurogram of vasoconstrictor sympathetic nerve activity
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For 5 minutes at the end of both treatments
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Cardiac baroreflex gain [ms/mmHg]
Time Frame: For 5 minutes at the end of both treatments
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Ratio between the changes in ECG RR interval and systolic blood pressure
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For 5 minutes at the end of both treatments
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Sympathetic baroreflex gain [bursts/mmHg]
Time Frame: For 5 minutes at the end of both treatments
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Ratio between the changes in burst frequency and diastolic blood pressure
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For 5 minutes at the end of both treatments
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Sympathetic excitability [bursts]
Time Frame: For 3 minutes at the end of both treatments
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Increase in burst frequency elicited by isometric exercise (handgrip)
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For 3 minutes at the end of both treatments
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NE [nM]
Time Frame: After 20 minutes of supine rest at the end of both treatments
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Venous plasma norepinephrine level
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After 20 minutes of supine rest at the end of both treatments
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
GLS [%]
Time Frame: For 10 seconds at the end of both treatments
|
Echocardiography: Global longitudinal strain as assessed using the speckle tracking technique |
For 10 seconds at the end of both treatments
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E/E' [ratio]
Time Frame: For 10 seconds at the end of both treatments
|
Echocardiography: E = mitral peak velocity of early filling E' = early diastolic mitral annular velocity (mean of E' lateral and E' septal) E and E' are obtained from 3 or 5 heart cycles with sinus rhythm or atrial fibrillation, respectively. |
For 10 seconds at the end of both treatments
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sPAP [mmHg]
Time Frame: For 10 seconds at the end of both treatments
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Echocardiography: Systolic pulmonary arterial pressure obtained from 3 or 5 heart cycles with sinus rhythm or atrial fibrillation, respectively. |
For 10 seconds at the end of both treatments
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HR variability [ms²]
Time Frame: For 5 minutes at the end of both treatments
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ECG RR-interval oscillations
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For 5 minutes at the end of both treatments
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BP variability [mmHg²]
Time Frame: For 5 minutes at the end of both treatments
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Blood pressure oscillations
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For 5 minutes at the end of both treatments
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Echocardiographic parameters
Time Frame: For 20 minutes at the end of both treatments
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Cardiac dimension and function as assessed by echocardiography
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For 20 minutes at the end of both treatments
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Collaborators and Investigators
Sponsor
Collaborators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- M17-05-LCZ-ARNI
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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