Trial Outcomes & Findings for Study of Efficacy and Safety of LCZ696 in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction (NCT NCT02468232)

Last Updated: 2023-12-08

Results Overview

Composite endpoint is defined as either cardiovascular (CV) death or heart failure (HF) hospitalization in Japanese patients with chronic heart failure (CHF) and reduced ejection fraction. The composite endpoint events occurred on and after End-of-study (EOS) declaration were reported by investigators but those events were not required to be adjudicated by Clinical Endpoint Committee (CEC) and not included in the efficacy analysis.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

225 participants

Primary outcome timeframe

up to 40 months

Results posted on

2023-12-08

Participant Flow

It was estimated that approximately 370 patients would be screened in order to randomize 220 patients (110 patients in each arm), as the screen or run-in failure rate was anticipated to be approximately 40%. It was anticipated that approximately 180 subjects would complete the core part of the study \& majority of them would be enrolled into the open-label extension (OLE).

Overall, 307 patients were screened, and 71 patients discontinued prior to the screening epoch completion. Thus, 236 patients entered the run-in epoch, with 11 patients being run-in failures.

Participant milestones

Participant milestones
Measure	LCZ696 Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Core Part of Study STARTED	112	113	0	0
Core Part of Study Randomized Patients	112	113	0	0
Core Part of Study Mis-randomized Patients	1	1	0	0
Core Part of Study Discont. From Randomized Treatment (Rand. Set)	21	19	0	0
Core Part of Study Discont. From Rand. Treatment (Full Analysis Set)	20	18	0	0
Core Part of Study COMPLETED	91	94	0	0
Core Part of Study NOT COMPLETED	21	19	0	0
OLE Part of Study STARTED	0	0	79	71
OLE Part of Study COMPLETED	0	0	65	59
OLE Part of Study NOT COMPLETED	0	0	14	12

Reasons for withdrawal

Reasons for withdrawal
Measure	LCZ696 Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Core Part of Study Adverse Event	0	1	0	0
Core Part of Study Death	20	17	0	0
Core Part of Study Technical Problems	1	1	0	0
OLE Part of Study Adverse Event	0	0	4	5
OLE Part of Study Death	0	0	4	2
OLE Part of Study Physician Decision	0	0	4	0
OLE Part of Study Subject/Guardian decision	0	0	2	5

Baseline Characteristics

Study of Efficacy and Safety of LCZ696 in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.	Total n=223 Participants Total of all reporting groups
Age, Continuous	68.97 years STANDARD_DEVIATION 9.717 • n=5 Participants	66.70 years STANDARD_DEVIATION 10.938 • n=7 Participants	—	—	67.83 years STANDARD_DEVIATION 10.388 • n=21 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	16 Participants n=7 Participants	—	—	31 Participants n=21 Participants
Sex: Female, Male Male	96 Participants n=5 Participants	96 Participants n=7 Participants	—	—	192 Participants n=21 Participants
Race/Ethnicity, Customized Japanese	111 Participants n=5 Participants	112 Participants n=7 Participants	—	—	223 Participants n=21 Participants

PRIMARY outcome

Timeframe: up to 40 months

Composite endpoint is defined as either cardiovascular (CV) death or heart failure (HF) hospitalization in Japanese patients with chronic heart failure (CHF) and reduced ejection fraction. The composite endpoint events occurred on and after End-of-study (EOS) declaration were reported by investigators but those events were not required to be adjudicated by Clinical Endpoint Committee (CEC) and not included in the efficacy analysis.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Number of Participants Who Had CEC (Clinical Endpoint Committee) Confirmed Composite Endpoints Primary composite	30 Participants	28 Participants	0 Participants	0 Participants
Number of Participants Who Had CEC (Clinical Endpoint Committee) Confirmed Composite Endpoints Cardiovascular (CV) Death	13 Participants	11 Participants	0 Participants	0 Participants
Number of Participants Who Had CEC (Clinical Endpoint Committee) Confirmed Composite Endpoints 1st heart failure (HF) Hospitalization	25 Participants	20 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: up to 40 months

Composite endpoint is defined as either cardiovascular (CV) death or heart failure (HF) hospitalization in Japanese patients with chronic heart failure (CHF) and reduced ejection fraction. EAIR = n/T where n = Total number of events included in the analysis. T (100 patient years) = total up-to-event/censoring duration-time summarized over participants in the respective treatment group. The composite endpoint events occurred on and after EOS declaration were reported by investigators but those events were not required to be adjudicated by CEC and not included in the efficacy analysis.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Exposure-adjusted Incident Rate (EAIR) of CEC Confirmed Composite Endpoints Primary composite	11.376 Events per 100 patient-years Interval 7.676 to 16.24	10.497 Events per 100 patient-years Interval 6.975 to 15.17	—	—
Exposure-adjusted Incident Rate (EAIR) of CEC Confirmed Composite Endpoints Cardiovascular (CV) Death	4.410 Events per 100 patient-years Interval 2.348 to 7.542	3.734 Events per 100 patient-years Interval 1.864 to 6.681	—	—
Exposure-adjusted Incident Rate (EAIR) of CEC Confirmed Composite Endpoints 1st heart failure (HF) Hospitalization	9.480 Events per 100 patient-years Interval 6.135 to 13.995	7.498 Events per 100 patient-years Interval 4.58 to 11.579	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8 and Month 6

Population: FAS consists of all randomized patients with the exception for those patients who have not been qualified for randomization and have not received investigational drug, but have been inadvertently randomized into the study. This analysis is a longitudinal data analysis and all available data up to month 6 for each patient was used. Number of participants at each post-time point indicates the number of patients who have both baseline and post-time point values.

NT-proBNP is small protein produced in large amounts when the heart senses it needs to work harder, such as in heart failure. Change from baseline to the pre-defined time-points in logarithmic scale were analyzed using a repeated measures ANCOVA model with treatment, the stratification factor screening NT-proBNP classification recorded in the Interactive Web Response System (IWRS), visit and treatment-by-visit interaction as fixed effect factors and the logarithmic baseline biomarker value as a covariate, with a common unstructured covariance matrix among visits for each treatment. The analysis is using all available data up to month 6 based on likelihood method with an assumption of missing at random (MAR) for missing data. This record summarizes the estimates of ratio Post-baseline /Baseline NT-proBNP.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Key Secondary: Change From Baseline to the Pre-defined Time-points in Log-transformed Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Week 4 (n = 111, 110, 0, 0)	0.7672 ratio Interval 0.6988 to 0.8423	0.8862 ratio Interval 0.8071 to 0.9731	—	—
Key Secondary: Change From Baseline to the Pre-defined Time-points in Log-transformed Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Week 8 (n = 111, 108, 0, 0)	0.7798 ratio Interval 0.7123 to 0.8537	0.9134 ratio Interval 0.8339 to 1.0004	—	—
Key Secondary: Change From Baseline to the Pre-defined Time-points in Log-transformed Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Month 6 (n= 110, 106, 0, 0)	0.6947 ratio Interval 0.621 to 0.7771	0.8564 ratio Interval 0.7646 to 0.9592	—	—

SECONDARY outcome

Timeframe: up to 40 months

Composite endpoint is defined as either cardiovascular (CV) death or heart failure (HF) hospitalization in Japanese patients with chronic heart failure (CHF) and reduced ejection fraction. Worsening HF defined as: worsening signs and symptoms of HF requiring addition of a new drug for HF treatment, initiation of IV treatment, increase of diuretic dose for persistent use for ≥4 consecutive weeks, or institution of mechanical or circulatory support such as mechanical ventilation, ultrafiltration, hemodialysis, intra-aortic balloon pump or ventricular assist device. The composite endpoint events occurred on and after EOS declaration were reported by investigators but those events were not required to be adjudicated by CEC and not included in the efficacy analysis.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Key Secondary: Number of Participants With CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients) First triple composite endpoint	37 Participants	37 Participants	—	—
Key Secondary: Number of Participants With CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients) CV death	13 Participants	11 Participants	—	—
Key Secondary: Number of Participants With CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients) First HF Hospitalization	25 Participants	20 Participants	—	—
Key Secondary: Number of Participants With CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients) First worsening of HF in outpatient	12 Participants	14 Participants	—	—

SECONDARY outcome

Timeframe: up to 40 months

Worsening HF defined as: worsening signs and symptoms of HF requiring addition of a new drug for HF treatment, initiation of IV treatment, increase of diuretic dose for persistent use for ≥4 consecutive weeks, or institution of mechanical or circulatory support such as mechanical ventilation, ultrafiltration, hemodialysis, intra-aortic balloon pump or ventricular assist device. EAIR(Exposure-adjusted incidence rate per 100 patient years)= n/T: n: Total number of events included in the analysis. T(100 patient years): total up-to-event/censoring duration-time summarized over patients in the respective treatment group. The composite endpoint events occurred on and after EOS declaration were reported by investigators but those events were not required to be adjudicated by CEC and not included in the efficacy analysis.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Key Secondary: EAIR of CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients) First triple composite endpoint	14.725 Events per 100 patient-years Interval 10.368 to 20.297	14.479 Events per 100 patient-years Interval 10.194 to 19.957	—	—
Key Secondary: EAIR of CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients) CV death	4.410 Events per 100 patient-years Interval 2.348 to 7.542	3.734 Events per 100 patient-years Interval 1.864 to 6.681	—	—
Key Secondary: EAIR of CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients) First HF Hospitalization	9.480 Events per 100 patient-years Interval 6.135 to 13.995	7.498 Events per 100 patient-years Interval 4.58 to 11.579	—	—
Key Secondary: EAIR of CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients) First worsening of HF in outpatient	4.372 Events per 100 patient-years Interval 2.259 to 7.638	5.095 Events per 100 patient-years Interval 2.786 to 8.549	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8 and Month 6

Population: FAS consists of all randomized patients with the exception for those patients who have not been qualified for randomization and have not received investigational drug, but have been inadvertently randomized into the study. Number of participants at post-time point (i.e., n) indicates the number of patients who have post-time point values.

NYHA classification is a subjective physician's assessment of heart failure patient's functional capacity and symptomatic status. Class I - No limitation of physical activity. Class II - Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class III - Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV - Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases. The NYHA class change was analyzed as a three category ordinal variable with levels: "improved", "unchanged", and "worsened", defined by at least one class improvement, no change, at least one class worsening, in NYHA class, respectively. NYHA class after patients who died was categorized into "worsened".

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints Week 4 Improved (n = 111, 111, 0, 0)	8 Participants	10 Participants	—	—
Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints Week 4 Unchanged (n = 111, 111, 0, 0)	102 Participants	96 Participants	—	—
Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints Week 4 Worsened (n = 111, 111, 0, 0)	1 Participants	5 Participants	—	—
Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints Week 8 Improved (n = 111, 111, 0, 0)	15 Participants	12 Participants	—	—
Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints Week 8 Unchanged (n = 111, 111, 0, 0)	95 Participants	93 Participants	—	—
Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints Week 8 Worsened (n = 111, 111, 0, 0)	1 Participants	6 Participants	—	—
Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints Month 6 Improved (n = 111, 110, 0, 0)	19 Participants	18 Participants	—	—
Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints Month 6 Unchanged (n = 111, 110, 0, 0)	91 Participants	84 Participants	—	—
Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints Month 6 Worsened (n = 111, 110, 0, 0)	1 Participants	8 Participants	—	—

SECONDARY outcome

Timeframe: Baseline, Week 8 and Month 6

Population: FAS consists of all randomized patients with the exception for those patients who have not been qualified for randomization and have not received investigational drug, but have been inadvertently randomized into the study. FAS included all patients with at least one KCCQ data. This is a longitudinal data analysis and all available data for each patient was used. Number of patients at each post-time point (n) indicates the number of patients who have both baseline and post-time point values.

The KCCQ is a self-administered questionnaire and requires, on average, 4-6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL), each with different Likert scaling wording, including limitations, frequency, bother, change in condition, understanding, etc. The clinical summary score is a mean of the physical limitation and total symptom scores. The total symptom score is the mean of the symptom frequency and symptom burden scores. Each scale score (the physical limitation, symptom frequency or symptom burden) is calculated as the mean of its item scores and transformed to a 0-100 scale, with higher score indicating higher level of functioning. A score of 100 represents perfect health whereas a score of 0 represents dead. A change of 5 points on the scale scores, either as a group mean difference or an intra-individual change appears to be clinically significant.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Key Secondary: Change From Baseline in Clinical Summary Score for Heart Failure Symptoms and Physical Limitations Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ). Week 8 (n = 111, 111, 0, 0)	-0.0491 scores on a scale Standard Error 1.3522	-2.5946 scores on a scale Standard Error 1.3504	—	—
Key Secondary: Change From Baseline in Clinical Summary Score for Heart Failure Symptoms and Physical Limitations Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ). Month 6 (n = 111, 110, 0, 0)	-2.2216 scores on a scale Standard Error 1.5898	-3.4910 scores on a scale Standard Error 1.5911	—	—

SECONDARY outcome

Timeframe: up tp 40 months

Total number of CEC-confirmed CV death and total (first and recurrent) HF hospitalizations per patient was analyzed using the negative binomial regression model. CV deaths and HF hospitalizations occurred on and after EOS declaration were reported by investigators but those events were not required to be adjudicated by CEC and not included in the efficacy analysis.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Total Number of CEC Confirmed Composite of CV Death and Total (First and Recurrent) HF Hospitalizations for Heart Failure	0.1734 Events per patient Interval 0.1123 to 0.268	0.1994 Events per patient Interval 0.1295 to 0.307	—	—

SECONDARY outcome

Timeframe: Baseline, Month 6

Population: The Full Analysis Set (FAS) consists of all randomized patients with the exception for those patients who have not been qualified for randomization and have not received investigational drug, but have been inadvertently randomized into the study. Overall Number of Participants Analyzed' indicates the number of patients who have post-time point values.

The global assessment was derived from the 7-category classification of the global assessment of disease activity to a three-category classification: Improved (Markedly improved; moderately improved), Unchanged (Slightly improved, unchanged, slightly worsened), and Worsened (Moderately worsened, markedly worsened). The clinical composite assessment was defined as follows: * Improved: 1) If NYHA class decreased at least one level and Global Assessment was not worse at the selected visit and there was no major AE up to the selected visit; or 2) Global assessment was improved and NYHA class did not increase at the selected visit, and there was no major AE up to the selected visit. * Worsened: 1) If NYHA class increased at the selected visit; or 2) Global Assessment was worse at the selected visit; or 3) experienced a major AE up to the selected visit. * Unchanged: If neither "Improved" nor "Worsened".

Outcome measures

Outcome measures
Measure	LCZ696 n=110 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=110 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Number of Participants by Changes in Clinical Composite Score (as Assessed by NYHA Classification and Patient Global Assessment) at Predefined Timepoints Clinical composite assessment: Improved	23 Participants	21 Participants	—	—
Number of Participants by Changes in Clinical Composite Score (as Assessed by NYHA Classification and Patient Global Assessment) at Predefined Timepoints Clinical composite assessment: Unchanged	78 Participants	78 Participants	—	—
Number of Participants by Changes in Clinical Composite Score (as Assessed by NYHA Classification and Patient Global Assessment) at Predefined Timepoints Clinical composite assessment: Worsened	9 Participants	11 Participants	—	—

SECONDARY outcome

Timeframe: up to 40 months

The number of participants who died due to any cause. Deaths occurred on and after EOS declaration were reported by investigators but those events were not required to be adjudicated by CEC and not included in the efficacy analysis.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Number of Participants With All-cause Mortality	19 Participants	16 Participants	—	—

SECONDARY outcome

Timeframe: up to 40 months

EAIR (Exposure-adjusted incidence rate per 100 patient years)= n/T: n: Total number of events included in the analysis. T(100 patient years): total up-to-event/censoring duration-time summarized over patients in the respective treatment group. Deaths occurred on and after EOS declaration were reported by investigators but those events were not required to be adjudicated by CEC and not included in the efficacy analysis.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
EAIR of All-cause Mortality	6.445 Events per 100 patient-years Interval 3.881 to 10.065	5.431 Events per 100 patient-years Interval 3.104 to 8.82	—	—

SECONDARY outcome

Timeframe: up to 40 months

Percentage of participants with hospitalized admissions

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Percentage of Participants Hospitalized	62 Participants	62 Participants	—	—

SECONDARY outcome

Timeframe: up to 40 months

The number of hospital admission events per-participant per year was calculated as total number of hospital admission divided by total up-to-event/censoring duration-time summarized over patients.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Hospitalization Admissions Events Per-participant Per Year	0.5881 Hospitalization admissions per year Interval 0.4439 to 0.7792	0.5771 Hospitalization admissions per year Interval 0.4376 to 0.761	—	—

SECONDARY outcome

Timeframe: up to 40 months

The number of days in ICU per participant per year was calculated as total number of days in ICU divided by total up-to-event/censoring duration-time summarized over patients.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Days in Intensive Care Unit (ICU) Per Participant Per Year	0.8542 Days per year Interval 0.2662 to 2.7409	0.7943 Days per year Interval 0.2929 to 2.1541	—	—

SECONDARY outcome

Timeframe: up to 40 months

The percentage of participants who had re-hospitalizations.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Percentage of Re-hospitalizations 3 Events	12 Participants	4 Participants	—	—
Percentage of Re-hospitalizations 2 Events	10 Participants	16 Participants	—	—
Percentage of Re-hospitalizations 4 Events	2 Participants	4 Participants	—	—
Percentage of Re-hospitalizations >= 5 Events	10 Participants	11 Participants	—	—

SECONDARY outcome

Timeframe: up to 40 months

The number of emergency department/urgent care facility visits for HF per patient per year was calculated as total number of emergency department/urgent care facility visits for HF divided by total up-to-event/censoring duration-time summarized over patients.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Emergency Department/Urgent Care Facility Visits for HF Per Patient Per Year	0.0533 Visits per year Interval 0.0277 to 0.1025	0.1183 Visits per year Interval 0.0667 to 0.2097	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 2, 4, 8 and Month 6

Population: The Full Analysis Set (FAS) consists of all randomized patients with the exception for those patients who have not been qualified for randomization and have not received investigational drug, but have been inadvertently randomized into the study. Number of participants at each post-time point (i.e., n) indicates the number of patients who have both baseline and post-time point values.

NT-proBNP is small protein produced in large amounts when the heart senses it needs to work harder, such as in heart failure. Mean change from baseline (post-baseline value - baseline value) in plasma NT-proBNP was caluculated.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Change in Blood NT-proBNP From Baseline Week 2 (n = 111, 108, 0, 0)	-366.5766 pg/mL Standard Deviation 611.8846	-86.2222 pg/mL Standard Deviation 1997.9885	—	—
Change in Blood NT-proBNP From Baseline Week 4 ( n = 111, 110, 0, 0)	-233.9279 pg/mL Standard Deviation 725.9590	-224.8545 pg/mL Standard Deviation 2023.1202	—	—
Change in Blood NT-proBNP From Baseline Week 8 (n = 111, 108, 0, 0)	-252.0090 pg/mL Standard Deviation 590.5862	-234.2963 pg/mL Standard Deviation 1840.3993	—	—
Change in Blood NT-proBNP From Baseline Month 6 (110, 106, 0, 0)	-327.5000 pg/mL Standard Deviation 731.9563	-240.7264 pg/mL Standard Deviation 2041.3829	—	—

SECONDARY outcome

Timeframe: Baseline and Month 18

Procollagen Type III N-Terminal Propeptide (PIIINP) is a serum marker of collagen turnover, generated during the synthesis of type III collagen. Increased circulating PIIINP is a marker not only of muscle growth, but also of muscle repair and fibrosis. Mean change from baseline (post-baseline value - baseline value) in serum PIIINP was calculated.

Outcome measures

Outcome measures
Measure	LCZ696 n=103 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=100 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Change in Procollagen Type III N-Terminal Propeptide From Baseline	0.2914 ug/L Standard Deviation 1.9105	-0.0583 ug/L Standard Deviation 1.7774	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8 and Month 6

Urinary Cyclic GMP (cGMP) is a biomarker measured in the urine that reflects the activity of biomarkers such as BNP (Brain Natriuretic Peptide). First morning void (FMV) urine samples were collected. Mean change from baseline (post-baseline value - baseline value) in urine cGMP was calculated.

Outcome measures

Outcome measures
Measure	LCZ696 n=111 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril n=112 Participants Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Changes in Urine Cyclic Guanosine 3',5'-Monophosphate (cGMP) From Baseline Week 8 (n = 111, 107, 0, 0)	587.4414 nmol/L Standard Deviation 886.4691	-52.7944 nmol/L Standard Deviation 503.1090	—	—
Changes in Urine Cyclic Guanosine 3',5'-Monophosphate (cGMP) From Baseline Week 4 (n = 110, 109, 0, 0)	556.3182 nmol/L Standard Deviation 663.8357	-25.9725 nmol/L Standard Deviation 552.6414	—	—
Changes in Urine Cyclic Guanosine 3',5'-Monophosphate (cGMP) From Baseline Month 6 (n = 110, 102, 0, 0)	507.9182 nmol/L Standard Deviation 1169.4057	-41.9706 nmol/L Standard Deviation 512.6963	—	—

SECONDARY outcome

Timeframe: Month 4 of OLE

Population: FAS-Ext: The full analysis set for OLE epoch (FAS-Ext) included all subjects in the extension population who received at least one dose of the extension study drug.

The percentage of participants who reached target dose level (200 mg b.i.d.) at Week 8 and maintained at Month 4(OLE). This indicates how tolerabile to LCZ696 at target dose.

Outcome measures

Outcome measures
Measure	LCZ696 Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch n=79 Participants The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch n=71 Participants The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Percentage of Participants Reaching Target Dose Level 3 at Week 8 and Maintained at Month 4 (Open Label Extension (OLE))	—	—	51 Participants	52 Participants

SECONDARY outcome

Timeframe: OLE Baseline, Month 12 (OLE)

Population: FAS-Ext: The full analysis set for OLE epoch (FAS-Ext) included all subjects in the extension population who received at least one dose of the extension study drug.

Outcome measures

Outcome measures
Measure	LCZ696 Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch n=71 Participants The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch n=66 Participants The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Change in NYHA Classification From OLE Baseline (OLE) Improved	—	—	3 Participants	4 Participants
Change in NYHA Classification From OLE Baseline (OLE) Unchanged	—	—	64 Participants	60 Participants
Change in NYHA Classification From OLE Baseline (OLE) Worsened	—	—	4 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline, Month 12 (OLE)

Population: FAS-Ext: The full analysis set for OLE epoch (FAS-Ext) included all subjects in the extension population who received at least one dose of the extension study drug.

Key echocardiographic parameters: LAVi- left atrial volume index, LVEDVi- left ventricular end diastolic volume index, LVESVi- left ventricular end systolic volume index. A two-dimensional and doppler echo examination was done to assess echo parameters. Mean changes from baseline (post-baseline value - baseline value) in each parameter were calculated. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch n=79 Participants The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch n=71 Participants The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Change in Key Echocardiographic Parameters From OLE Baseline at Month 12 (OLE) LAVi (n = 0, 0, 67, 55)	—	—	-3.31 mL/m^2 Standard Deviation 11.679	-1.47 mL/m^2 Standard Deviation 12.389
Change in Key Echocardiographic Parameters From OLE Baseline at Month 12 (OLE) LVEDVi (n = 0, 0, 62, 53)	—	—	2.54 mL/m^2 Standard Deviation 18.712	0.99 mL/m^2 Standard Deviation 25.919
Change in Key Echocardiographic Parameters From OLE Baseline at Month 12 (OLE) LVESVi (n = 0, 0, 62, 53)	—	—	-2.32 mL/m^2 Standard Deviation 14.801	-2.65 mL/m^2 Standard Deviation 20.619

SECONDARY outcome

Timeframe: Baseline, Month 12 (OLE)

Population: FAS-Ext: The full analysis set for OLE epoch (FAS-Ext) included all subjects in the extension population who received at least one dose of the extension study drug.

Key echocardiographic parameter: LVEF- left ventricular ejection fraction. LVEF is a measurement expressed as a percentage of how much blood the left ventricle pumps out with each contraction. Mean changes from baseline (post-baseline value - baseline value) in LVEF were calculated.

Outcome measures

Outcome measures
Measure	LCZ696 Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch n=62 Participants The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch n=53 Participants The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Change in Cardiac Measurements by Key Echocardiographic Parameter LVEF, From OLE Baseline at Month 12 (OLE)	—	—	3.97 Percentage of ejected blood Standard Deviation 6.647	3.46 Percentage of ejected blood Standard Deviation 5.984

SECONDARY outcome

Timeframe: Baseline, Weeks 2-4, Week 8, Months 4 and 12 (OLE)

Population: FAS-Ext: The full analysis set for OLE epoch (FAS-Ext) included all subjects in the extension population who received at least one dose of the extension study drug. Number of participants at each post-time point (i.e., n) indicates the number of patients who have both baseline and post-time point values.

BNP is small protein produced in large amounts when the heart senses it needs to work harder, such as in heart failure. Mean change from baseline (post-baseline value - OLE baseline value) in plasma BNP was calculated.

Outcome measures

Outcome measures
Measure	LCZ696 Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch n=79 Participants The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch n=71 Participants The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Change in B-type Natriuretic Peptide (BNP) From OLE Baseline to Predefined Timepoints (OLE) Weeks 2-4 (n = 0, 0, 78, 70)	—	—	-81.78 pg/mL Standard Deviation 402.754	89.77 pg/mL Standard Deviation 336.742
Change in B-type Natriuretic Peptide (BNP) From OLE Baseline to Predefined Timepoints (OLE) Week 8 (n = 0, 0, 78, 68)	—	—	-34.86 pg/mL Standard Deviation 509.893	170.87 pg/mL Standard Deviation 492.707
Change in B-type Natriuretic Peptide (BNP) From OLE Baseline to Predefined Timepoints (OLE) Month 4 (n = 0,0, 76, 69)	—	—	12.86 pg/mL Standard Deviation 515.351	200.87 pg/mL Standard Deviation 672.071
Change in B-type Natriuretic Peptide (BNP) From OLE Baseline to Predefined Timepoints (OLE) Month 12 (n = 0,0, 71, 66)	—	—	115.11 pg/mL Standard Deviation 600.797	153.06 pg/mL Standard Deviation 479.813

SECONDARY outcome

Timeframe: Baseline, Weeks 2-4, Week 8, Months 4 and 12 (OLE)

NT-proBNP is small protein produced in large amounts when the heart senses it needs to work harder, such as in heart failure. Mean change from baseline (post-baseline value - OLE baseline value) in plasma NT-proBNP was calculated.

Outcome measures

Outcome measures
Measure	LCZ696 Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch n=79 Participants The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch n=71 Participants The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Change in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From OLE Baseline to Predefined Timepoints (OLE) Weeks 2-4 (n = 0, 0, 78, 70)	—	—	-235.73 pg/mL Standard Deviation 1642.510	-333.12 pg/mL Standard Deviation 829.689
Change in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From OLE Baseline to Predefined Timepoints (OLE) Week 8 (n = 0, 0, 78, 68	—	—	-219.47 pg/mL Standard Deviation 1876.166	-279.53 pg/mL Standard Deviation 806.447
Change in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From OLE Baseline to Predefined Timepoints (OLE) Month 4 (n = 0,0, 76, 69)	—	—	-83.49 pg/mL Standard Deviation 798.424	-280.35 pg/mL Standard Deviation 930.407
Change in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From OLE Baseline to Predefined Timepoints (OLE) Month 12 (n = 0,0, 71, 66)	—	—	266.43 pg/mL Standard Deviation 1201.239	-358.98 pg/mL Standard Deviation 995.833

SECONDARY outcome

Timeframe: Weeks 2-4, Week 8, Months 4 and 12 (OLE)

Urinary Cyclic GMP (cGMP) is a biomarker measured in the urine that reflects the activity of biomarkers such as BNP (Brain Natriuretic Peptide). Spot urine samples were collected. Mean change from baseline (post-baseline value - OLE baseline value) in urine cGMP was calculated.

Outcome measures

Outcome measures
Measure	LCZ696 Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch n=79 Participants The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch n=71 Participants The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Change in Urine cGMP From OLE Baseline to Predefined Timepoints (OLE) Weeks 2-4 (n = 0, 0, 78, 69)	—	—	106.78 nmol/L Standard Deviation 1139.886	411.16 nmol/L Standard Deviation 956.355
Change in Urine cGMP From OLE Baseline to Predefined Timepoints (OLE) Week 8 (n = 0, 0, 78, 68)	—	—	142.59 nmol/L Standard Deviation 1005.718	356.41 nmol/L Standard Deviation 885.854
Change in Urine cGMP From OLE Baseline to Predefined Timepoints (OLE) Month 4 (n = 0, 0, 76, 68)	—	—	176.50 nmol/L Standard Deviation 1023.525	580.40 nmol/L Standard Deviation 1021.542
Change in Urine cGMP From OLE Baseline to Predefined Timepoints (OLE) Month 12 (n = 0, 0, 71, 66)	—	—	-131.86 nmol/L Standard Deviation 1284.239	493.21 nmol/L Standard Deviation 1024.247

SECONDARY outcome

Timeframe: Month 12

Association (using the Pearson correlation coefficient) between change from OLE baseline in log-transformed NT-proBNP and echocardiographic parameters (LAVi, LVEDVi, LVESVi \& LVEF)

Outcome measures

Outcome measures
Measure	LCZ696 Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.	Enalapril Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.	LCZ696 (Core) OLE Epoch n=79 Participants The patients who received LCZ696 in the core part of the study and continued to receive LCZ696 in the open-label extension (OLE) are referred to as LCZ (core) group. These patients received open-label LCZ696 in the OLE phase.	Enalapril (Core) OLE Epoch n=71 Participants The subjects who received enalapril in the core part and then switched to LCZ696 in the OLE are referred to as ENA (core) group. These patients switched from enalapril and received open-label LCZ696 in the OLE phase.
Association Between Change in NT-proBNP Concentration and Change in Echocardiographic Parameters From OLE Baseline at Month 12 (OLE) NT-proBNP / LVEF (n = 0, 0, 62, 53)	—	—	-0.2582 Peason's correlation Interval -0.4756 to -0.0069	0.0233 Peason's correlation Interval -0.2488 to 0.2915
Association Between Change in NT-proBNP Concentration and Change in Echocardiographic Parameters From OLE Baseline at Month 12 (OLE) NT-proBNP / LAVi( =0,0, 67, 55)	—	—	0.0178 Peason's correlation Interval -0.2235 to 0.2567	0.0640 Peason's correlation Interval -0.2054 to 0.3232
Association Between Change in NT-proBNP Concentration and Change in Echocardiographic Parameters From OLE Baseline at Month 12 (OLE) NT-proBNP/ LVEDVi (n = 0, 0, 62, 53)	—	—	-0.1869 Peason's correlation Interval -0.4159 to 0.0675	-0.0059 Peason's correlation Interval -0.2757 to 0.2649
Association Between Change in NT-proBNP Concentration and Change in Echocardiographic Parameters From OLE Baseline at Month 12 (OLE) NT-proBNP / LVESVi (n = 0, 0, 62, 53)	—	—	-0.0775 Peason's correlation Interval -0.3205 to 0.1762	0.0047 Peason's correlation Interval -0.266 to 0.2746

Adverse Events

LCZ696

Serious events: 64 serious events

Other events: 108 other events

Deaths: 20 deaths

Enalapril

Serious events: 61 serious events

Other events: 108 other events

Deaths: 17 deaths

LCZ696 (Core) OLE Epoch

Serious events: 38 serious events

Other events: 67 other events

Deaths: 4 deaths

Enalapril (Core) OLE Epoch

Serious events: 26 serious events

Other events: 64 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

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