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Heart FailurePhase 2ARNI-SyNCT03415906

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

A Phase 2 study testing sacubitril+valsartan and valsartan in people with Heart Failure, run by Hannover Medical School at 1 site in Germany.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Heart Failure
What is being tested?
sacubitril+valsartan and valsartan
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
1 siteGermany
Study dates
14 Dec 2017to 6 Sep 2018
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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
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  • 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)

Trial locations and contacts

1 site in 1 country.

Germany1 site

  • Clinical Research Center Hannover, Hannover Medical School

    Hanover, 30625

Other trials in Germany

About this study

Official title: 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.

Read the detailed description

Thirty-five heart-failure patients will be included in a prospective, monocentric, active-controlled, double-blind, cross-over study with randomized sequence of treatments sacubitril+valsartan or valsartan alone. After open-label dose finding and washout patients will be randomly assigned to the treatment sequence [sac+val --> val] or [val --> sac+val]. The two treatment periods of 4 weeks duration will be separated by 2 weeks of washout. At the end of both treatments the state of the cardiovascular system and its control will be measured.

Conditions
Heart Failure
Being tested
sacubitril+valsartan, valsartan
Keywords
angiotensin receptor blocker, neprilysin inhibition, sympathetic activity, baroreflex, microneurography, functional MRI
Medical subject headings
Heart Failure

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • sacubitril+valsartanCombination product

    Combined angiotensin receptor + neprilysin inhibition

  • valsartanDrug

    Also called Angiotensin receptor blocker (AT1-receptor blocker)

    Angiotensin receptor inhibition alone

Study groups in NCT03415906
Study groupRoleWhat they receive
sacubitril+valsartanExperimentalCombined angiotensin receptor and neprilysin inhibition
Receives: Combination Product: sacubitril+valsartan
valsartanActive comparatorAngiotensin receptor inhibition alone
Receives: Drug: valsartan

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. MSNA burst frequency [bursts/min]

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

    Measured: For 5 minutes at the end of both treatments

Secondary outcomes (9)

  1. DBP [mmHg]

    Diastolic blood pressure

    Measured: For 5 minutes at the end of both treatments

  2. PVN activity [unitless]

    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.

    Measured: For 20 minutes at the end of both treatments

  3. NTS activity [unitless]

    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.

    Measured: For 20 minutes at the end of both treatments

  4. MSNA burst incidence [bursts/100 heartbeats]

    Bursts of vasoconstrictor sympathetic nerve activity normalized to heart rate

    Measured: For 5 minutes at the end of both treatments

  5. MSNA burst area [au/min]

    Area under the bursts in the integrated neurogram of vasoconstrictor sympathetic nerve activity

    Measured: For 5 minutes at the end of both treatments

  6. Cardiac baroreflex gain [ms/mmHg]

    Ratio between the changes in ECG RR interval and systolic blood pressure

    Measured: For 5 minutes at the end of both treatments

  7. Sympathetic baroreflex gain [bursts/mmHg]

    Ratio between the changes in burst frequency and diastolic blood pressure

    Measured: For 5 minutes at the end of both treatments

  8. Sympathetic excitability [bursts]

    Increase in burst frequency elicited by isometric exercise (handgrip)

    Measured: For 3 minutes at the end of both treatments

  9. NE [nM]

    Venous plasma norepinephrine level

    Measured: After 20 minutes of supine rest at the end of both treatments

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Jan 2018
  2. Study start14 Dec 2017
  3. Primary completion6 Sep 2018
  4. Study completion6 Sep 2018

Why it stopped: Difficulties in recruiting patients

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Model description
Prospective, monocentric, active-controlled, double-blind, cross-over with randomized sequence of treatments
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03415906
Sponsor's protocol ID
M17-05-LCZ-ARNI
Acronym
ARNI-Sy
Status last verified
Oct 2018
First submitted
2 Jan 2018
Last updated
9 Oct 2018
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing sacubitril+valsartan and valsartan in people with Heart Failure, run by Hannover Medical School at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 9 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

MSNA burst frequency [bursts/min] (time frame: For 5 minutes at the end of both treatments). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03415906.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Oct 2018.

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