This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure

Study Overview
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Brief Summary
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The study will evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure (NYHA Class II - IV and EF =< 35%).

Official Title
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A Multicenter, Randomized, Double-blind, Parallel Group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality in Patients With Chronic Heart Failure and Reduced Ejection Fraction

Conditions
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Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
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* Drug: LCZ696 200 mg BID
* Drug: Enalapril 10 mg BID


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must give written informed consent before any assessment is performed. Outpatients ≥ 18 years of age, male or female. Patients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction (EF =< 35%) and elevated BNP. 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. Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks. Exclusion Criteria: Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer. 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. Previous history of intolerance to recommended target doses of ACEIs or ARBs Known history of angioedema. Requirement of treatment with both ACEIs and ARBs. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy). Symptomatic hypotension and/or a SBP < 100 mmHg. Estimated GFR < 30 mL/min/1.73m2 as measured by the simplified MDRD formula Serum potassium > 5.2 mmol/L. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCZ696<br>single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period | Drug: LCZ696 200 mg BID<br>* LCZ696 200 mg BID<br>|
| Active Comparator: Enalapril<br>single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period | Drug: Enalapril 10 mg BID<br>* Enalapril 10 mg BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | Number of participants that had first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization due to HF. | up to 51 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients - All-cause Mortality | Number of patients - All-cause mortality. All-cause mortality is common in Heart Failure HF patients this measures how many patients had this event. The data is on FAS population up to March 31, 2014 | up to 51 months | 
| Number of Patients Reported With Adjudicated Primary Causes of Death | Number of patients reported with adjudicated primary causes of death. The data is on Randomization population up to March 31, 2014 | up to 51 months | 
| Change From Baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score | Change from baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. KCCQ clinical summary score is a composite assessment of physical limitations and total symptom scores. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. | Baseline, Month 8 | 
| Number of Patients With First Confirmed Renal Dysfunction | Number of patients with first confirmed renal dysfunction | up to 51 months | 
| Percentage of Participants With New Onset of Atrial Fibrillation (AF) | Percentage of participants with New Onset of Atrial Fibrillation The new onset atrial fibrillation (AF) analysis was based on a subset of FAS: i.e., for patients without a history of AF at baseline (patients with a history of AF were excluded from this analysis). | up to 51 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BNP, chronic heart failure, cardiovascular death, hospitalization, outcome study, KCCQ, eGFR