Chronic heart failure with reduced left ventricular ejection fraction (NYHA II-III) MedDRA version: 20.0 Level: LLT Classification code 10078289 Term: Heart failure with reduced ejection fraction System Organ Class: 100000004849
Conditions
Interventions
Trade Name: Entresto® 49 mg/51 mg Filmtabletten
Product Name: Sacubitril/Valsartan
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SACUBITRIL
CAS Number: 149709-62-6
Sponsors
Hannover Medical School
Eligibility
Sex/Gender
All
Inclusion 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 (any measurement made within the past 6 month using echocardiography, MUGA, CT scanning, MRT or ventricular angiography is acceptable, provided no subsequent measurement above 40%) 4. ACE inhibitor or ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks before visit 1 (screening) 5. Stable dose of a beta-blocker for at least 4 weeks before visit 1 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 • 40 IU/l and serum estrogen=65 years) yes F.1.3.1 Number of subjects for this age range 21
Exclusion criteria
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. Known history of angioedema 3. Recent acute decompensated heart failure within 2 months before screening (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy) 4. Symptomatic hypotension and/or office systolic BP 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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To test the hypothesis that angiotensin-neprilysin inhibition (Sacubitril + Valsartan) reduces sympathetic activity compared to standard heart failure therapy (Valsartan).;Secondary Objective: To test the hypotheses that angiotensin-neprilysin inhibition: 1. is non-inferior regarding diastolic blood pressure reduction (end of period – baseline) assuming a non-inferiority-margin of 4 mmHg 2. reduces activity of pre-motor sympathetic brainstem centers as measured by fMRI 3. reduces resting muscle sympathetic nerve activity (MSNA) burst incidence 4. reduces MSNA burst area 5. improves baroreflex regulation of heart rate (HR) 6. improves baroreflex regulation of MSNA 7. attenuates MSNA increases during sympathetic stimuli (e.g. handgrip testing) 8. reduces venous plasma norepinephrine levels Assessment of safety: SAEs, AEs and safety laboratory tests will be collected throughout the study.;Primary end point(s): Central sympathetic nerve traffic measured as MSNA in bursts/minute;Timepoint(s) of evaluation of this end point: week 4 and week 10 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Diastolic blood pressure 2. Activity of sympathetic brainstem centers measured by fMRI 3. MSNA burst incidence 4. MSNA burst area 5. Cardiac baroreflex gain 6. Sympathetic baroreflex gain 7. Change in MSNA in bursts/min during handgrip 8. Venous plasma norepinephrine level;Timepoint(s) of evaluation of this end point: All secondary endpoints will be evaluated at week 4 and 10. | — |
Countries
Germany
Contacts
Public ContactMarkus May
MHH CRC Core Facility, Hannover Medical School
Outcome results
None listed