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

NCT ID: NCT03415906

Last Updated: 2018-10-09

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-12-14
• Study Completion Date: 2018-09-06

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

sacubitril+valsartan

Combined angiotensin receptor and neprilysin inhibition

Group Type: EXPERIMENTAL

sacubitril+valsartan

Intervention Type: COMBINATION_PRODUCT

Combined angiotensin receptor + neprilysin inhibition

valsartan

Angiotensin receptor inhibition alone

Group Type: ACTIVE_COMPARATOR

valsartan

Intervention Type: DRUG

Angiotensin receptor inhibition alone

Interventions

sacubitril+valsartan

Combined angiotensin receptor + neprilysin inhibition

Intervention Type: COMBINATION_PRODUCT

valsartan

Angiotensin receptor inhibition alone

Intervention Type: DRUG

Other Intervention Names

Angiotensin receptor blocker (AT1-receptor blocker)

Eligibility Criteria

Inclusion Criteria

1. Women or men at the age ≥ 18 years, ≤ 80 years and able to give written informed consent

2. Heart failure NYHA class II-III

3. Ejection fraction of 40 % or less

4. 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.)

5. Stable dose of a beta-blocker over the last 4 weeks unless contraindicated or not tolerated

6. Patient has to be in sinus rhythm

7. Patients capable of understanding the investigational nature, potential risks and benefits of the clinical trial

8. 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

9. Signed written informed consent and willingness to comply with treatment and follow- up procedures.

Exclusion Criteria

1. 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

2. History of angioedema

3. Recent acute decompensated heart failure within 2 months before screening

4. Symptomatic hypotension and/or office systolic BP <110 mmHg at screening measured according to the recommendations of the European Society of Hypertension

5. Combined intake of an ACE inhibitor and ARB over the last 4 weeks

6. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m²

7. Concomitant medication with Aliskiren in patients with Diabetes or patients with eGFR < 60 mL/min/1.73 m²

8. Serum potassium >5.2 mmol/L at Visit 1 (screening)

9. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid, or other major cardiovascular surgery, PCI, or carotid angioplasty within the 3 months before screening

10. History of heart transplant or on a transplant list or with LV assistance device

11. History of severe pulmonary disease

12. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1

13. Presence of hemodynamically significant mitral and/or aortic valve disease/ left ventricular outflow tract obstruction, except mitral regurgitation secondary to LV dilatation

14. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs

15. 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

16. Contraindications precluding microneurography measurements, such as relevant peripheral neuropathy as judged by the investigator

17. Pregnancy or lactation period

18. Current participation in any other clinical trial or participation in another clinical trial within 30 days before screening

19. Known or suspected hypersensitivity to any of the active substances or any excipients of the investigational medicinal products

20. Vulnerable subjects (i.e. persons under any administrative or legal supervision or persons kept in detention)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

DLR German Aerospace Center

OTHER

Sponsor Role: collaborator

Hannover Medical School

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Clinical Research Center Hannover, Hannover Medical School

Hanover, , Germany

Countries

Germany

Other Identifiers

M17-05-LCZ-ARNI

Identifier Type: -

Identifier Source: org_study_id