chronic heart failure and reduced ejection fraction MedDRA version: 20.0 Level: LLT Classification code 10008502 Term: CHF System Organ Class: 100000004849
Conditions
Sponsors
Novartis Pharma GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients must give written informed consent before any assessment is performed and must be willing and capable to comply with all study procedures. 2. Outpatients = 18 years of age, male or female. 3. Patients with a diagnosis of CHF NYHA class III and reduced ejection fraction: • LVEF = 40% at Visit 1 (any local measurement, made within the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular angiography is acceptable, provided no subsequent measurement above 40%) 4. Reduced ability to exercise, evidenced by VO2peak = 18 ml/min per kg 5. Patients must be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks before Visit 1 • For this protocol doses of other ACEIs considered to be equivalent to enalapril 10 mg/d include benazepril 20 mg/d, captopril 100 mg/d, cilazapril 2.5 mg/d, fosinopril 20 mg/d, lisinopril 10 mg/d, moexipril 7.5 mg/d, perindopril 4 mg/d, quinapril 20 mg/d, ramipril 5 mg/d, trandolapril 2 mg/d, and zofenopril 30 mg/d. • For this protocol doses of ARBs considered to be equivalent to enalapril 10 mg/d include candesartan 16 mg/d, eprosartan 400 mg/d, irbesartan 150 mg/d, losartan 50 mg/d, olmesartan 10 mg/d, telmisartan 40 mg/d, and valsartan 160 mg/d. 6. Patients must be treated for CHF according to local guideline recommendations and should be stable on treatment and dose for at least 4 weeks prior to Visit 1. Treatment according to guideline should include: • A ß-blocker, unless contraindicated or not tolerated, (reason should be documented for patients not on CHF target doses per local guidelines, or in absence of that medication). • An aldosterone antagonist should also be considered in all patients, taking account of renal function, serum potassium and tolerability. If given, the dose of aldosterone antagonist should be optimized according to guideline recommendations and patient tolerability. • Ivabradine should also be considered in all patients with heart rates above 70 beats per minute. If given, the dose of ivabradine should be optimized according to guideline recommendations and patient tolerability. • Other evidence-based therapy for heart failure should also be considered e.g. cardiac resynchronization therapy and an implantable cardioverter-defibrillator in selected patients, as recommended by guidelines. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 100 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 100
Exclusion criteria
Exclusion criteria: 1. Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-lives of enrolment, whichever is longer 2. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs 3. Previous history of intolerance to recommended target doses of ACEIs or ARBs 4. Known history of angioedema 5. Requirement of treatment with both ACEIs and ARBs 6. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy) 7. Symptomatic hypotension and/or a SBP 5.2 mmol/L at Visit 1 (screening) or Visit 3 (randomization) 10. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1 11. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1. 12. Implantation of a cardiac resynchronization therapy pacemaker (CRT-P) or a cardiac resynchronization therapy defibrillator (CRT-D) or upgrading of an existing conventional pacemaker or an implantable cardioverter defibrillator (ICD) to CRT device within 3 months prior Visit 1 or intent to implant such a device. Also, patients who had implantation of a conventional pacemaker or an ICD or had a revision of a pacemaker or other device leads within 1 month before Visit 1 are excluded. 13. Heart transplant or ventricular assistance device (VAD) or intent to transplant within the 14 week study duration (on transplant list with high urgency (HU) status) or to implant a VAD. 14. History or current diagnosis of severe pulmonary disease, including chronic obstructive pulmonary disease (COPD). 15. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months prior to Visit 1 16. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1 17. Symptomatic bradycardia or second or third degree heart block without a pacemaker 18. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation 19. Presence of other hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis 20. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs 21. Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x ULN at Visit 1, severe hepatic insufficiency (classification Child-Pugh C), biliary cirrhosis, cholestasis (current or anamnestic evidence), history of hepatic encephalopathy, history of esophageal varices, or history of portocaval shunt 22. Active treatment with cholestyramine or colestipol resins 23. Presence of any other disease with a life expectancy of < 5 years 24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): The primary endpoint is change of VO2peak compared to baseline measurements (adjusted to body weight) after 3 months of treatment. ;Timepoint(s) of evaluation of this end point: 3 months;Main Objective: The primary objective of this study is to demonstrate the superiority of LCZ696 200 mg bid compared to enalapril 10 mg bid in improving exercise tolerance (VO2peak, adjusted to body weight) as assessed by cardiopulmonary exercise testing (CPET) in patients with stable chronic heart failure (NYHA class III) and reduced ejection fraction (LVEF = 40%) after 3 months treatment.;Secondary Objective: Secondary objectives of this study are To demonstrate the superiority LCZ696 versus enalapril regarding improvement of exercise tolerance (VO2peak, adjusted to body weight) as assessed by cardiopulmonary exercise testing (CPET) in patients with chronic heart failure after 6 weeks treatment. To compare LCZ696 versus enalapril on the following CPET parameters: ? Change of VE/VCO2 slope after 6 weeks and 3 months ? Change in exercise capacity (Watt) at VAT after 6 weeks and 3 months ? Rate of perceived exertion during exercise (Borg Scale) after 3 months To assess the safety and tolerability of LCZ696 in patients with stable chronic heart failure with NYHA class III and reduced ejection fraction (LVEF = 40%) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary objectives of this study are To demonstrate the superiority LCZ696 versus enalapril regarding improvement of exercise tolerance (VO2peak, adjusted to body weight) as assessed by cardiopulmonary exercise testing (CPET) in patients with chronic heart failure after 6 weeks treatment. To compare LCZ696 versus enalapril on the following CPET parameters: ? Change of VE/VCO2 slope after 6 weeks and 3 months ? Change in exercise capacity (Watt) at VAT after 6 weeks and 3 months ? Rate of perceived exertion during exercise (Borg Scale) after 3 months To assess the safety and tolerability of LCZ696 in patients with stable chronic heart failure with NYHA class III and reduced ejection fraction (LVEF = 40%);Timepoint(s) of evaluation of this end point: 6 weeks + 3 months | — |
Countries
Germany
Contacts
Public ContactMedizinischer Infoservice (MCC)
Novartis Pharma GmbH
Outcome results
None listed