E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008502 |
E.1.2 | Term | CHF |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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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 if LCZ696 is superior to enalapril in delaying time to first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization, in patients with CHF (NYHA class II – IV) and reduced ejection fraction |
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E.2.2 | Secondary objectives of the trial |
• To test whether LCZ696, compared to enalapril, improves the clinical summary score for HF symptoms and physical limitations (as assessed by the Kansas City Cardiomyopathy Questionnaire [KCCQ]) at 8 months.
• To test whether LCZ696 is superior to enalapril in delaying the time to all-cause mortality.
• To test whether LCZ696 is superior to enalapril in delaying time to first occurrence to either (1) a 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline, (2) >30 mL decline in eGFR relative to baseline, or (3) reaching end stage renal disease (ESRD).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Patients must give written informed consent before any assessment is performed.
2.Outpatients ≥ 18 years of age, male or female.
3.Patients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction:
o LVEF ≤ 35% 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 35%)
o BNP ≥ 150 pg/ml (or NT-proBNP ≥ 600 pg/ml) at Visit 1 OR BNP ≥ 100 pg/mL (or NT-proBNP ≥ 400 pg/ml) at Visit 1 and a hospitalization for HF within the last 12 months
4.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
o 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.
o 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.
5. Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1 (reason should be documented for patients not on CHF target doses per local guidelines, or in absence of that medication)
6. An aldosterone antagonist should also be considered in all patient, taking account of renal function, serum potassium and tolerability. If given, the dose of aldosterone antagonist should be optimized according to the guideline recommendations and patient tolerability, and should be stable for at least 4 weeks prior to Visit 1. Other evidence-based therapy for hearth failure should also be considered e.g. cardiac resynchronization therapy and an implantable cardioverter-deffibrilator in selected patients, as recommended by guidelines.
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E.4 | Principal exclusion criteria |
1.Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, 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 < 100 mmHg at Visit 1 (screening) or < 95 mmHg at Visit 3 or at Visit 5 (randomization)
8.Estimated GFR < 30 mL/min/1.73m2 as measured by the simplified MDRD formula at Visit 1 (screening), Visit 3 (end of enalapril run-in), or Visit 5 (end of LCZ696 run-in and randomization) or > 35% decline in eGFR between Visit 1 and Visit 3 or between Visit 1 and Visit 5
9.Serum potassium > 5.2 mmol/L at Visit 1 (screening) or > 5.4 mmol/L at Visit 3 or Visit 5 (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 CRTP or a CRTD or upgrading of an existing conventional pacemaker or an implantable cardioverter defibrillator (ICD) to CRT within 3 months before 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 months before Visit 1 are excluded.
13. Heart transplant or ventricular assistance device (VAD) or intent to transplant (on transplant list) or implant a VAD.
14.History of severe pulmonary disease
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, including but not limited to any of the following:
o History of active inflammatory bowel disease during the 12 months before Visit 1.
o Current duodenal or gastric ulcers during the 3 months prior to Visit 1
o Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x ULN at Visit 1, history of hepatic encephalopathy, history of esophageal varices, or history of portacaval shunt
o Active treatment with cholestyramine or colestipol resins
21.Presence of any other disease with a life expectancy of < 5 years
22.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 laboratory test (> 5 mIU/mL)
For other criteria see Protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- change in the clinical summary score for HF symptoms and physical limitations (as assessed by KCCQ)
- time to all-cause mortality
- time to occurrence of renal dysfunction
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
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 | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 21 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 260 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
China |
Colombia |
Costa Rica |
Czech Republic |
Denmark |
Ecuador |
Egypt |
Estonia |
Finland |
France |
Germany |
Guatemala |
Hungary |
Iceland |
India |
Israel |
Italy |
Jordan |
Korea, Democratic People's Republic of |
Latvia |
Lebanon |
Lithuania |
Malaysia |
Mexico |
Netherlands |
New Zealand |
Norway |
Panama |
Peru |
Philippines |
Poland |
Portugal |
Romania |
Russian Federation |
Saudi Arabia |
Serbia |
Slovakia |
South Africa |
Sweden |
Taiwan |
Thailand |
Tunisia |
Turkey |
Ukraine |
United Arab Emirates |
United Kingdom |
Venezuela, Bolivarian Republic of |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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This study is an event driven, outcomes trial. The end of the study will occur when the pre-specified number of patients achieves the primary composite endpoint of CV deaths or hospitalizations for heart failure (2,410 patients), unless the study is terminated early because of a statistically significant results in the efficacy interim analysis or because of a critical safety concern that arises at any of the safety interim analyses. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |