| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic heart failure with reduced left ventricular ejection fraction (NYHA II-III) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic heart failure with reduced left ventricular ejection fraction |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10078289 |
| E.1.2 | Term | Heart failure with reduced ejection fraction |
| E.1.2 | System Organ Class | 100000004849 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To test the hypothesis that angiotensin-neprilysin inhibition (Sacubitril + Valsartan) reduces sympathetic activity compared to standard heart failure therapy (Valsartan). |
|
| E.2.2 | Secondary objectives of the trial |
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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
• < 50 years and in postmenopausal state ≥ 1 year with serum FSH > 40 IU/l and serum 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. |
|
| E.4 | Principal 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 <110 mmHg at visit 1
5. Combined intake of an ACE inhibitor and ARB over the last 4 weeks before visit 1
6. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² as measured by the simplified MDRD forumla
7. Concomitant medication with Aliskiren in patients with Diabetes or patients with eGFR < 60 mL/min/1.73 m² as measured by the simplified MDRD forumla
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) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Central sympathetic nerve traffic measured as MSNA in bursts/minute |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary endpoints will be evaluated at week 4 and 10.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
