Trial Outcomes & Findings for Sodium Excretion of LCZ696 in Patients With Hypertension; Heart Failure and Healthy Volunteers (NCT NCT01353508)

Last Updated: 2015-11-23

Results Overview

Urine was collected in 12-hour intervals, and of each pooled 24-hour (daily) sample, sodium concentration was measured. The measure type used for this outcome measure (OM) was Geometric Least square Means (LSM).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

32 participants

Primary outcome timeframe

day 1

Results posted on

2015-11-23

Participant Flow

In each of the HF and HTN cohorts, 16 participants (total = 32) received LCZ696 or Valsartan in period 1. Then, there was a cross-over where participants received LCZ96 or Valsartan in period 2.

Participant milestones

Participant milestones
Measure	LCZ696 to Valsartan - Heart Failure (HF) Cohort Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan to LCZ696 - HF Cohort Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 to Valsartan - Hypertension (HTN) Cohort Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan to LCZ696 - HTN Cohort Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Period 1 - First Intervention (7 Days) STARTED	8	8	8	8
Period 1 - First Intervention (7 Days) COMPLETED	8	8	8	7
Period 1 - First Intervention (7 Days) NOT COMPLETED	0	0	0	1
Period 2 - Second Intervention (7 Days) STARTED	8	8	8	7
Period 2 - Second Intervention (7 Days) COMPLETED	7	8	8	7
Period 2 - Second Intervention (7 Days) NOT COMPLETED	1	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	LCZ696 to Valsartan - Heart Failure (HF) Cohort Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan to LCZ696 - HF Cohort Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 to Valsartan - Hypertension (HTN) Cohort Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan to LCZ696 - HTN Cohort Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Period 1 - First Intervention (7 Days) Adverse Event	0	0	0	1
Period 2 - Second Intervention (7 Days) Withdrawal by Subject	1	0	0	0

Baseline Characteristics

Sodium Excretion of LCZ696 in Patients With Hypertension; Heart Failure and Healthy Volunteers

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LCZ696 to Valsartan - Heart Failure (HF) Cohort n=8 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan to LCZ696 - HF Cohort n=8 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 to Valsartan - Hypertension (HTN) Cohort n=8 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan to LCZ696 - HTN Cohort n=8 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.	Total n=32 Participants Total of all reporting groups
Age, Continuous	63.3 Years STANDARD_DEVIATION 10.15 • n=93 Participants	67.6 Years STANDARD_DEVIATION 9.07 • n=4 Participants	58.0 Years STANDARD_DEVIATION 8.02 • n=27 Participants	61.6 Years STANDARD_DEVIATION 8.40 • n=483 Participants	62.6 Years STANDARD_DEVIATION 8.86 • n=36 Participants
Sex: Female, Male Female	2 Participants n=93 Participants	0 Participants n=4 Participants	5 Participants n=27 Participants	2 Participants n=483 Participants	9 Participants n=36 Participants
Sex: Female, Male Male	6 Participants n=93 Participants	8 Participants n=4 Participants	3 Participants n=27 Participants	6 Participants n=483 Participants	23 Participants n=36 Participants

PRIMARY outcome

Timeframe: day 1

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
24-hour Urinary Sodium Excretion	220.58 mmol/24 hours Interval 182.64 to 266.41	198.73 mmol/24 hours Interval 163.5 to 241.56	177.40 mmol/24 hours Interval 152.65 to 206.15	146.18 mmol/24 hours Interval 126.42 to 169.03

PRIMARY outcome

Timeframe: 7 day-cummulative (days 1 through 7)

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Cumulative 7-day Urinary Sodium Excretion	1020.57 mmol/7 days Interval 903.47 to 1152.84	1114.18 mmol/7 days Interval 983.37 to 1262.39	906.81 mmol/7 days Interval 839.94 to 979.0	943.26 mmol/7 days Interval 873.62 to 1018.45

SECONDARY outcome

Timeframe: day 1

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

Urine was collected in 12-hour intervals, and of each pooled 24-hour (daily) sample, urine volume was measured. The measure type used for this OM was Geometric LSM.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
24-hour Diuresis	3199.37 mL/24 hours Interval 2662.17 to 3844.96	2874.36 mL/24 hours Interval 2375.61 to 3477.82	3382.94 mL/24 hours Interval 2859.86 to 4001.7	2393.61 mL/24 hours Interval 2034.84 to 2815.64

SECONDARY outcome

Timeframe: 7-day cumulative (days 1 through 7)

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

Urine was collected in 12-hour intervals, and of each pooled 24-hour (daily) sample, urine volume was measured. The measure type used for this OM was Geometric LSM.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
7-day Cumulative Diuresis	12347.92 mL Interval 10842.81 to 14062.48	13180.02 mL Interval 11539.55 to 15053.71	16980.05 mL Interval 15627.59 to 18449.54	15265.35 mL Interval 14048.28 to 16587.87

SECONDARY outcome

Timeframe: day 1, day 6, day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

cGMP was analyzed at a central laboratory. The measure type used for this OM was Geometric LSM.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Urinary Cyclic Guanosine Monophosphate (cGMP) Excretion Over 24 Hours Day 1	1851.79 nmol/24 hours Interval 1504.96 to 2278.56	884.99 nmol/24 hours Interval 713.93 to 1097.03	1085.76 nmol/24 hours Interval 867.64 to 1358.71	557.53 nmol/24 hours Interval 448.87 to 692.51
Urinary Cyclic Guanosine Monophosphate (cGMP) Excretion Over 24 Hours Day 6	1467.67 nmol/24 hours Interval 1153.25 to 1867.79	865.62 nmol/24 hours Interval 674.39 to 1111.07	863.32 nmol/24 hours Interval 707.64 to 1053.25	562.11 nmol/24 hours Interval 460.85 to 685.63
Urinary Cyclic Guanosine Monophosphate (cGMP) Excretion Over 24 Hours Day 7	1571.02 nmol/24 hours Interval 1331.84 to 1853.15	859.07 nmol/24 hours Interval 723.03 to 1020.72	1107.04 nmol/24 hours Interval 869.95 to 1408.76	603.90 nmol/24 hours Interval 474.68 to 768.3

SECONDARY outcome

Timeframe: 2, 4, 6 and 12 hours post dose on day 1; 24 hours post dose on day 2; 2, 4, 6 and 12 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

MR-proANP was analyzed at a central laboratory.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker Day 1, 2.0 hours post dose	-7.04 Percentage change Interval -12.21 to -1.87	2.08 Percentage change Interval -3.48 to 7.63	-10.11 Percentage change Interval -17.41 to -2.82	-1.66 Percentage change Interval -7.99 to 4.68
Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker Day 1, 4.0 hrs post dose	-17.39 Percentage change Interval -24.68 to -10.1	-6.74 Percentage change Interval -14.32 to 0.84	-12.68 Percentage change Interval -25.45 to 0.08	-7.33 Percentage change Interval -19.27 to 4.61
Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker Day 1, 6.0 hours post dose	-23.99 Percentage change Interval -31.64 to -16.33	-10.16 Percentage change Interval -18.08 to -2.23	-17.82 Percentage change Interval -25.16 to -10.48	-4.52 Percentage change Interval -11.6 to 2.56
Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker Day 1, 12.0 hrs post dose	-27.58 Percentage change Interval -38.93 to -16.22	-7.48 Percentage change Interval -19.26 to 4.29	-19.77 Percentage change Interval -32.56 to -6.98	-15.20 Percentage change Interval -27.1 to -3.31
Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker Day 2, 24.0 hrs post dose	-25.13 Percentage change Interval -35.53 to -14.73	-14.53 Percentage change Interval -25.28 to -3.78	-17.30 Percentage change Interval -33.46 to -1.13	-9.45 Percentage change Interval -24.39 to 5.5
Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker Day 7, 0.0 hours	-21.27 Percentage change Interval -29.72 to -12.81	-2.54 Percentage change Interval -11.3 to 6.21	-16.03 Percentage change Interval -28.52 to -3.53	0.44 Percentage change Interval -11.59 to 12.46
Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker Day 7, 4.0 hours post dose	-24.35 Percentage change Interval -35.18 to -13.52	1.64 Percentage change Interval -9.62 to 12.91	-19.34 Percentage change Interval -31.2 to -7.49	-2.56 Percentage change Interval -13.9 to 8.78
Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker Day 7, 6.0 hours post dose	-23.40 Percentage change Interval -33.98 to -12.82	-3.53 Percentage change Interval -14.54 to 7.48	-20.84 Percentage change Interval -33.62 to -8.05	-1.98 Percentage change Interval -14.25 to 10.28
Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker Day 7, 12.0 hours post dose	-20.95 Percentage change Interval -33.1 to -8.8	-12.65 Percentage change Interval -25.27 to -0.03	-23.09 Percentage change Interval -35.9 to -10.28	-10.27 Percentage change Interval -22.61 to 2.06

SECONDARY outcome

Timeframe: 0.5, 1, 2, 4, 6 and 12 hours post dose on day 1; 24 hours post dose on day 2; 0, 4, 6 and 12 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

BNP was analyzed at a central laboratory.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 1, 0.5 hour post dose	72.32 Percentage change Interval -70.26 to 214.9	-8.93 Percentage change Interval -151.85 to 133.99	-10.75 Percentage change Interval -28.59 to 7.08	-5.94 Percentage change Interval -23.59 to 11.71
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 1, 1.0 hr post dose	121.85 Percentage change Interval -86.02 to 329.72	-0.83 Percentage change Interval -209.19 to 207.53	1218.56 Percentage change Interval -760.23 to 3197.35	-33.19 Percentage change Interval -1865.92 to 1799.53
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 1, 2.0 hours post dose	176.35 Percentage change Interval -85.34 to 438.04	21.92 Percentage change Interval -215.63 to 259.47	31.10 Percentage change Interval 8.44 to 53.76	-0.38 Percentage change Interval -21.37 to 20.61
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 1, 4.0 hrs post dose	50.12 Percentage change Interval 30.22 to 70.02	-1.78 Percentage change Interval -21.01 to 17.44	38.82 Percentage change Interval 18.71 to 58.92	11.06 Percentage change Interval -7.56 to 29.68
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 1, 6.0 hrs post dose	130.62 Percentage change Interval -10.46 to 271.7	11.09 Percentage change Interval -130.33 to 152.51	68.23 Percentage change Interval 11.48 to 124.97	7.97 Percentage change Interval -44.59 to 60.52
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 1, 12.0 hrs post dose	90.58 Percentage change Interval 28.51 to 152.66	30.07 Percentage change Interval -32.15 to 92.29	85.93 Percentage change Interval 23.34 to 148.52	8.51 Percentage change Interval -48.97 to 65.99
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 2, 24 hrs post dose	102.88 Percentage change Interval -84.18 to 289.93	5.18 Percentage change Interval -174.46 to 184.81	-0.66 Percentage change Interval -31.34 to 30.02	-20.61 Percentage change Interval -47.16 to 5.94
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 7, 0.0 hr	190.96 Percentage change Interval -100.59 to 482.51	27.75 Percentage change Interval -264.49 to 320.0	14.20 Percentage change Interval -28.81 to 57.21	-7.19 Percentage change Interval -48.17 to 33.79
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 7, 4.0 hrs post dose	220.38 Percentage change Interval -72.28 to 513.04	34.44 Percentage change Interval -249.44 to 318.31	34.92 Percentage change Interval -6.58 to 76.42	5.20 Percentage change Interval -34.59 to 44.99
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 7, 6.0 hrs post dose	195.06 Percentage change Interval -94.9 to 485.02	46.75 Percentage change Interval -257.14 to 350.63	7.78 Percentage change Interval -33.49 to 49.04	7.82 Percentage change Interval -29.68 to 45.32
Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker Day 7, 12.0 hrs post dose	236.05 Percentage change Interval -173.38 to 645.47	70.31 Percentage change Interval -334.37 to 474.99	38.45 Percentage change Interval -13.98 to 90.88	25.79 Percentage change Interval -24.48 to 76.06

SECONDARY outcome

Timeframe: 2, 4, 6 and 12 hours post dose on day 1; 24 hours post dose on day 2; 0, 4, 6 and 12 hours post dose on day 7

Population: The HF arms only of the Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis. MR-proADM is considered a biomarker for HF only; therefore, the HTN cohort was not assessed.

MR-proADM was analyzed at a central laboratory.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker Day 1, 2.0 hours post dose	8.04 Percentage change Interval -0.34 to 16.42	-2.87 Percentage change Interval -11.53 to 5.79	—	—
Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker Day 1, 4.0 hrs post dose	21.22 Percentage change Interval 11.38 to 31.06	-8.22 Percentage change Interval -18.03 to 1.59	—	—
Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker Day 1, 6.0 hrs post dose	20.18 Percentage change Interval 10.05 to 30.31	-8.81 Percentage change Interval -18.9 to 1.27	—	—
Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker Day 1, 12.0 hrs post dose	40.70 Percentage change Interval 22.25 to 59.15	7.61 Percentage change Interval -10.84 to 26.05	—	—
Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker Day 2, 24 hrs post dose	57.28 Percentage change Interval 42.29 to 72.26	0.72 Percentage change Interval -14.26 to 15.7	—	—
Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker Day 7, 0.0 hrs	61.28 Percentage change Interval 47.35 to 75.21	1.38 Percentage change Interval -12.07 to 14.83	—	—
Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker Day 7, 4.0 hrs post dose	51.71 Percentage change Interval 39.67 to 63.74	-5.27 Percentage change Interval -16.9 to 6.36	—	—
Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker Day 7, 6.0 hrs post dose	48.22 Percentage change Interval 36.26 to 60.19	-3.63 Percentage change Interval -14.89 to 7.64	—	—
Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker Day 7, 12.0 hrs post dose	69.45 Percentage change Interval 50.7 to 88.2	2.15 Percentage change Interval -16.6 to 20.9	—	—

SECONDARY outcome

Timeframe: 2, 4, 6, 8 and 12 hours post dose on day 1; day 2; 0, 4, 6, 8 and 12 hours post dose on day 7

ProCNP was analyzed at a central laboratory.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 1, 2.0 hrs post dose	0.35 Percentage change Interval -6.33 to 7.03	-1.01 Percentage change Interval -8.16 to 6.13	—	—
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 1, 4.0 hours post dose	34.58 Percentage change Interval 19.36 to 49.79	-6.02 Percentage change Interval -22.28 to 10.25	—	—
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 1, 6.0 hrs post dose	67.85 Percentage change Interval 42.32 to 93.37	-16.19 Percentage change Interval -43.85 to 11.48	—	—
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 1, 8.0 hrs post dose	123.75 Percentage change Interval 87.53 to 159.98	-9.87 Percentage change Interval -48.59 to 28.86	—	—
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 1, 12.0 hrs post dose	190.36 Percentage change Interval 148.95 to 231.78	15.55 Percentage change Interval -29.0 to 60.09	—	—
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 2, 24 hrs post dose	218.81 Percentage change Interval 163.62 to 274.01	4.99 Percentage change Interval -54.79 to 64.78	—	—
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 7, 0.0 hour	244.20 Percentage change Interval 186.26 to 302.14	0.09 Percentage change Interval -61.85 to 62.04	—	—
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 7, 4.0 hours post dose	216.61 Percentage change Interval 159.66 to 273.56	-8.94 Percentage change Interval -69.82 to 51.95	—	—
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 7, 6.0 hrs post dose	211.21 Percentage change Interval 151.36 to 271.07	-18.17 Percentage change Interval -82.15 to 45.82	—	—
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 7, 8.0 hrs post dose	241.99 Percentage change Interval 181.22 to 302.76	-11.30 Percentage change Interval -76.27 to 53.67	—	—
Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker Day 7, 12.0 hrs post dose	278.58 Percentage change Interval 214.45 to 342.71	0.88 Percentage change Interval -67.68 to 69.44	—	—

SECONDARY outcome

Timeframe: 12 hours post dose on day 1; 24 hours post dose on day 2; 0 and 12 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

CT-proET-1 was analyzed at a central laboratory.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Percent Change From Baseline in C-terminal-proendothelin-1 (CT-proET-1) Biomarker Day 1, 12.0 hours post dose	36.39 Percentage change Interval 26.14 to 46.65	2.51 Percentage change Interval -8.14 to 13.16	108.87 Percentage change Interval 5.82 to 211.92	54.07 Percentage change Interval -38.42 to 146.57
Percent Change From Baseline in C-terminal-proendothelin-1 (CT-proET-1) Biomarker Day 2, 24.0 hours post dose	32.44 Percentage change Interval 19.41 to 45.47	11.41 Percentage change Interval -2.76 to 25.59	123.45 Percentage change Interval 36.65 to 210.25	38.70 Percentage change Interval -41.78 to 119.19
Percent Change From Baseline in C-terminal-proendothelin-1 (CT-proET-1) Biomarker Day 7, 0.0 hour	31.98 Percentage change Interval 19.53 to 44.42	0.62 Percentage change Interval -11.85 to 13.09	94.76 Percentage change Interval 17.45 to 172.06	41.77 Percentage change Interval -32.97 to 116.5
Percent Change From Baseline in C-terminal-proendothelin-1 (CT-proET-1) Biomarker Day 7, 12.0 hours post dose	41.75 Percentage change Interval 26.81 to 56.69	7.05 Percentage change Interval -8.97 to 23.08	117.84 Percentage change Interval 30.76 to 204.92	61.90 Percentage change Interval -22.4 to 146.2

SECONDARY outcome

Timeframe: 2, 4, 6 and 12 hours post dose on day 1; 24 hours post dose on day 2; 0, 4, 6 and 12 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

NT-proBNP was analyzed at a central laboratory.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker Day 1, 2.0 hours post dose	3.06 Percentage change Interval -1.8 to 7.92	6.87 Percentage change Interval 1.87 to 11.88	5.10 Percentage change Interval -1.1 to 11.31	8.32 Percentage change Interval 2.32 to 14.32
Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker Day 1, 4.0 hours post dose	2.68 Percentage change Interval -5.3 to 10.66	13.21 Percentage change Interval 5.02 to 21.4	44.79 Percentage change Interval -11.93 to 101.51	22.14 Percentage change Interval -32.65 to 76.93
Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker Day 1, 6.0 hours post dose	3.71 Percentage change Interval -8.15 to 15.57	21.70 Percentage change Interval 9.59 to 33.8	12.58 Percentage change Interval -4.17 to 29.33	21.21 Percentage change Interval 5.03 to 37.39
Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker Day 1, 12.0 hours post dose	17.15 Percentage change Interval -3.58 to 37.89	42.32 Percentage change Interval 20.94 to 63.7	61.46 Percentage change Interval 3.83 to 119.09	33.17 Percentage change Interval -22.28 to 88.62
Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker Day 2, 24 hours post dose	-21.85 Percentage change Interval -35.37 to -8.33	23.51 Percentage change Interval 9.48 to 37.54	8.61 Percentage change Interval -20.73 to 37.95	-4.41 Percentage change Interval -32.64 to 23.81
Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker Day 7, 0.0 hour	-19.57 Percentage change Interval -34.08 to -5.05	2.29 Percentage change Interval -12.74 to 17.32	-10.14 Percentage change Interval -35.77 to 15.48	-0.13 Percentage change Interval -25.77 to 25.51
Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker Day 7, 4.0 hours post dose	-14.60 Percentage change Interval -30.67 to 1.47	14.85 Percentage change Interval -1.78 to 31.49	-8.10 Percentage change Interval -35.21 to 19.01	19.83 Percentage change Interval -7.29 to 46.95
Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker Day 7, 6.0 hours post dose	-15.05 Percentage change Interval -32.53 to 2.43	17.34 Percentage change Interval -0.75 to 35.44	-9.42 Percentage change Interval -37.4 to 18.57	20.47 Percentage change Interval -6.63 to 47.58
Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker Day 7, 12.0 hours post dose	1.37 Percentage change Interval -22.83 to 25.56	46.05 Percentage change Interval 20.87 to 71.22	12.22 Percentage change Interval -26.18 to 50.62	47.27 Percentage change Interval 8.85 to 85.68

SECONDARY outcome

Timeframe: 6 and 12 hours post dose on day 1; 24 hours post dose on day 2; 0, 6 and 12 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

Aldosterone was analyzed at a central laboratory.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Percent Change From Baseline in Aldosterone Biomarker Day 7, 0.0 hour	111.21 Percentage change Interval 16.31 to 206.11	21.68 Percentage change Interval -77.33 to 120.69	49.91 Percentage change Interval -12.58 to 112.4	5.61 Percentage change Interval -55.0 to 66.22
Percent Change From Baseline in Aldosterone Biomarker Day 1, 6.0 hours post dose	71.15 Percentage change Interval 29.66 to 112.64	-14.63 Percentage change Interval -56.02 to 26.77	90.51 Percentage change Interval -39.1 to 220.12	72.92 Percentage change Interval -48.38 to 194.22
Percent Change From Baseline in Aldosterone Biomarker Day 1, 12.0 hours post dose	208.06 Percentage change Interval 44.03 to 372.1	8.36 Percentage change Interval -155.05 to 171.77	249.13 Percentage change Interval 4.3 to 493.96	325.31 Percentage change Interval 96.75 to 553.86
Percent Change From Baseline in Aldosterone Biomarker Day 2, 24.0 hours post dose	168.32 Percentage change Interval 65.01 to 271.63	71.73 Percentage change Interval -35.08 to 178.55	438.28 Percentage change Interval -67.61 to 944.17	524.93 Percentage change Interval 55.45 to 994.41
Percent Change From Baseline in Aldosterone Biomarker Day 7, 6.0 hours post dose	65.22 Percentage change Interval 7.48 to 122.95	24.58 Percentage change Interval -31.7 to 80.87	24.47 Percentage change Interval -104.07 to 153.01	107.60 Percentage change Interval -16.47 to 231.67
Percent Change From Baseline in Aldosterone Biomarker Day 7, 12.0 hours post dose	238.32 Percentage change Interval -46.1 to 522.74	230.06 Percentage change Interval -58.04 to 518.17	147.89 Percentage change Interval -4.4 to 300.19	152.37 Percentage change Interval 4.74 to 300.0

SECONDARY outcome

Timeframe: 2, 4, 6 and 12 hours post dose on day 1; 24 hours post dose on day 2; 0, 4, 6 and 12 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

Urine was collected in 12-hour intervals, and of each pooled 24-hour (daily) sample, sodium, potassium, albumin and calcium were measured.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Calcium, day 1, 2.0 hours post dose	-0.05 Percentage change Interval -1.24 to 1.13	-1.40 Percentage change Interval -2.62 to -0.17	0.51 Percentage change Interval -1.0 to 2.01	0.08 Percentage change Interval -1.38 to 1.53
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Calcium, day 1, 4.0 hours post dose	-2.19 Percentage change Interval -3.78 to -0.6	-2.46 Percentage change Interval -4.11 to -0.81	0.76 Percentage change Interval -1.39 to 2.91	0.27 Percentage change Interval -1.79 to 2.33
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Calcium, day 1, 6.0 hours post dose	-3.69 Percentage change Interval -5.19 to -2.19	-4.03 Percentage change Interval -5.59 to -2.48	-2.22 Percentage change Interval -3.89 to -0.55	-2.49 Percentage change Interval -4.1 to -0.89
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Calcium, day 1, 12.0 hours post dose	-2.80 Percentage change Interval -4.24 to -1.37	-1.34 Percentage change Interval -2.83 to 0.16	1.77 Percentage change Interval -0.4 to 3.94	0.82 Percentage change Interval -1.27 to 2.91
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Calcium, day 2, 24 hours post dose	-2.09 Percentage change Interval -4.21 to 0.02	0.44 Percentage change Interval -1.72 to 2.6	2.06 Percentage change Interval -0.42 to 4.55	1.34 Percentage change Interval -1.06 to 3.73
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Calcium, day 7, 0.0 hour	-0.34 Percentage change Interval -2.75 to 2.07	-1.11 Percentage change Interval -3.6 to 1.38	-5.82 Percentage change Interval -8.28 to -3.36	-6.19 Percentage change Interval -8.65 to -3.73
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Calcium, day 7, 4.0 hours post dose	-2.45 Percentage change Interval -4.09 to -0.81	-2.17 Percentage change Interval -3.87 to -0.47	-8.46 Percentage change Interval -10.95 to -5.98	-7.42 Percentage change Interval -9.9 to -4.94
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Calcium, day 7, 6.0 hours post dose	-4.30 Percentage change Interval -5.65 to -2.95	-3.53 Percentage change Interval -4.93 to -2.12	-9.12 Percentage change Interval -11.54 to -6.7	-9.89 Percentage change Interval -12.32 to -7.47
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Calcium, day 7, 12.0 hours post dose	-3.41 Percentage change Interval -4.94 to -1.88	-1.27 Percentage change Interval -2.86 to 0.32	-4.63 Percentage change Interval -6.89 to -2.36	-4.99 Percentage change Interval -7.25 to -2.73
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Chloride, day 1, 2.0 hours post dose	-0.33 Percentage change Interval -1.05 to 0.39	-0.47 Percentage change Interval -1.22 to 0.28	-0.35 Percentage change Interval -0.96 to 0.27	0.22 Percentage change Interval -0.38 to 0.81
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Chloride, day 1, 4.0 hours post dose	-1.35 Percentage change Interval -2.07 to -0.64	-0.61 Percentage change Interval -1.36 to 0.14	0.05 Percentage change Interval -0.62 to 0.72	0.41 Percentage change Interval -0.23 to 1.05
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Chloride, day 1, 6.0 hours post dose	-0.66 Percentage change Interval -1.35 to 0.03	-0.42 Percentage change Interval -1.14 to 0.3	-0.48 Percentage change Interval -1.15 to 0.19	0.05 Percentage change Interval -0.59 to 0.7
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Chloride, day 1, 12.0 hours post dose	0.46 Percentage change Interval -0.49 to 1.41	1.44 Percentage change Interval 0.45 to 2.42	-0.93 Percentage change Interval -1.7 to -0.16	-0.15 Percentage change Interval -0.92 to 0.62
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Chloride, day 2, 24 hours post dose	0.49 Percentage change Interval -0.23 to 1.22	0.73 Percentage change Interval -0.02 to 1.48	0.11 Percentage change Interval -0.82 to 1.04	0.58 Percentage change Interval -0.34 to 1.51
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Chloride, day 7, 0.0 hour	1.46 Percentage change Interval 0.4 to 2.53	1.28 Percentage change Interval 0.19 to 2.37	0.89 Percentage change Interval 0.17 to 1.62	0.63 Percentage change Interval -0.09 to 1.36
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Chloride, day 7, 4.0 hours post dose	0.47 Percentage change Interval -0.96 to 1.89	0.22 Percentage change Interval -1.26 to 1.69	-0.05 Percentage change Interval -0.86 to 0.75	0.28 Percentage change Interval -0.5 to 1.07
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Chloride, day 7, 6.0 hours post dose	0.87 Percentage change Interval -0.29 to 2.03	1.32 Percentage change Interval 0.11 to 2.52	-0.21 Percentage change Interval -1.0 to 0.58	-0.86 Percentage change Interval -1.68 to -0.04
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Chloride, day 7, 12.0 hours post dose	0.98 Percentage change Interval -0.12 to 2.09	1.20 Percentage change Interval 0.06 to 2.35	-1.16 Percentage change Interval -2.08 to -0.25	-1.48 Percentage change Interval -2.43 to -0.53
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Potassium, day 1, 2.0 hours post dose	1.96 Percentage change Interval -0.71 to 4.63	-1.25 Percentage change Interval -4.01 to 1.51	-1.20 Percentage change Interval -3.86 to 1.45	1.69 Percentage change Interval -0.86 to 4.24
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Potassium, day 1, 4.0 hours post dose	-0.16 Percentage change Interval -3.73 to 3.41	-0.11 Percentage change Interval -3.8 to 3.58	0.42 Percentage change Interval -6.1 to 6.95	1.11 Percentage change Interval -5.17 to 7.39
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Potassium, day 1, 6.0 hours post dose	-2.91 Percentage change Interval -5.82 to 0.01	-5.88 Percentage change Interval -8.9 to -2.87	-0.63 Percentage change Interval -8.29 to 7.02	-2.61 Percentage change Interval -10.0 to 4.79
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Potassium, day 1, 12.0 hours post dose	6.63 Percentage change Interval -0.02 to 13.28	15.27 Percentage change Interval 8.4 to 22.15	18.57 Percentage change Interval 10.49 to 26.64	19.96 Percentage change Interval 11.85 to 28.08
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Potassium, day 2, 24.0 hours post dose	2.06 Percentage change Interval -1.44 to 5.56	0.14 Percentage change Interval -3.48 to 3.76	7.70 Percentage change Interval 1.23 to 14.18	7.00 Percentage change Interval 0.51 to 13.49
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Potassium, day 7, 0.0 hour	1.06 Percentage change Interval -2.8 to 4.93	-1.55 Percentage change Interval -5.55 to 2.45	-0.47 Percentage change Interval -4.7 to 3.76	1.29 Percentage change Interval -2.93 to 5.52
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Potassium, day 7, 4.0 hours post dose	-2.16 Percentage change Interval -5.21 to 0.89	-2.93 Percentage change Interval -6.08 to 0.22	3.61 Percentage change Interval -5.71 to 12.94	0.28 Percentage change Interval -8.6 to 9.16
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Potassium, day 7, 6.0 hours post dose	-3.23 Percentage change Interval -6.47 to 0.0	-5.16 Percentage change Interval -8.49 to -1.84	-4.20 Percentage change Interval -10.85 to 2.45	-4.14 Percentage change Interval -11.06 to 2.78
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Potassium, day 7, 12.0 hours post dose	17.22 Percentage change Interval 9.58 to 24.86	12.32 Percentage change Interval 4.37 to 20.26	18.19 Percentage change Interval 7.38 to 29.01	19.28 Percentage change Interval 8.12 to 30.45
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Sodium, day 1, 2.0 hours post dose	-1.09 Percentage change Interval -1.68 to -0.5	-0.67 Percentage change Interval -1.28 to -0.05	-0.63 Percentage change Interval -1.1 to -0.16	-0.17 Percentage change Interval -0.63 to 0.29
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Sodium, day 1, 4.0 hours post dose	-1.82 Percentage change Interval -2.52 to -1.13	-1.18 Percentage change Interval -1.9 to -0.45	-0.18 Percentage change Interval -0.84 to 0.48	-0.04 Percentage change Interval -0.67 to 0.59
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Sodium, day 1, 6.0 hours post dose	-1.47 Percentage change Interval -2.09 to -0.84	-1.12 Percentage change Interval -1.77 to -0.47	-0.62 Percentage change Interval -1.2 to -0.04	-0.17 Percentage change Interval -0.73 to 0.39
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Sodium, day 1, 12.0 hours post dose	-0.17 Percentage change Interval -0.74 to 0.39	0.48 Percentage change Interval -0.11 to 1.07	-0.12 Percentage change Interval -0.91 to 0.68	0.14 Percentage change Interval -0.66 to 0.93
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Sodium, day 2, 24.0 hours post dose	0.03 Percentage change Interval -0.78 to 0.84	1.06 Percentage change Interval 0.22 to 1.9	0.85 Percentage change Interval 0.24 to 1.45	1.24 Percentage change Interval 0.63 to 1.84
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Sodium, day 7, 0.0 hour	1.21 Percentage change Interval 0.23 to 2.18	1.36 Percentage change Interval 0.35 to 2.37	0.69 Percentage change Interval 0.05 to 1.33	0.84 Percentage change Interval 0.2 to 1.48
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Sodium, day 7, 4.0 hours post dose	-0.25 Percentage change Interval -1.46 to 0.95	-0.89 Percentage change Interval -2.14 to 0.37	-0.81 Percentage change Interval -1.57 to -0.05	-0.16 Percentage change Interval -0.89 to 0.57
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Sodium, day 7, 6.0 hours post dose	0.01 Percentage change Interval -1.17 to 1.19	-0.19 Percentage change Interval -1.42 to 1.05	-0.74 Percentage change Interval -1.36 to -0.13	-0.86 Percentage change Interval -1.49 to -0.23
Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) Sodium, day 7, 12.0 hours post dose	0.34 Percentage change Interval -0.62 to 1.29	0.78 Percentage change Interval -0.22 to 1.77	-0.41 Percentage change Interval -1.23 to 0.42	-1.04 Percentage change Interval -1.89 to -0.2

SECONDARY outcome

Timeframe: 4, 6 and 12 hours post dose on day 1; 24 hours post dose on day 2; 0, 4, 6 and 12 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

Blood plasma creatinine was analyzed at a central laboratory.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Percent Change From Baseline in Blood Plasma Creatinine Day 1, 4.0 hours post dose	-7.06 Percentage change Interval -9.03 to -5.1	-3.55 Percentage change Interval -5.56 to -1.54	-7.48 Percentage change Interval -9.28 to -5.68	-0.91 Percentage change Interval -2.65 to 0.83
Percent Change From Baseline in Blood Plasma Creatinine Day 1, 6.0 hrs post dose	-2.97 Percentage change Interval -5.49 to -0.46	-0.07 Percentage change Interval -2.67 to 2.54	-1.72 Percentage change Interval -5.41 to 1.96	4.40 Percentage change Interval 0.84 to 7.95
Percent Change From Baseline in Blood Plasma Creatinine Day 1, 12.0 hrs post dose	3.02 Percentage change Interval -1.96 to 8.0	5.36 Percentage change Interval 0.21 to 10.52	6.22 Percentage change Interval 1.9 to 10.54	9.23 Percentage change Interval 5.07 to 13.4
Percent Change From Baseline in Blood Plasma Creatinine Day 2, 24 hrs post dose	3.73 Percentage change Interval -1.37 to 8.83	4.02 Percentage change Interval -1.26 to 9.3	13.64 Percentage change Interval 8.44 to 18.84	6.18 Percentage change Interval 1.15 to 11.21
Percent Change From Baseline in Blood Plasma Creatinine Day 7, 0.0 hour	4.24 Percentage change Interval -6.71 to 15.19	0.55 Percentage change Interval -10.43 to 11.52	1.76 Percentage change Interval -1.74 to 5.27	1.71 Percentage change Interval -1.79 to 5.21
Percent Change From Baseline in Blood Plasma Creatinine Day 7, 4.0 hrs post dose	-1.47 Percentage change Interval -8.56 to 5.63	-5.09 Percentage change Interval -12.26 to 2.07	-3.02 Percentage change Interval -6.71 to 0.68	-1.28 Percentage change Interval -4.98 to 2.41
Percent Change From Baseline in Blood Plasma Creatinine Day 7, 6.0 hrs post dose	1.72 Percentage change Interval -6.15 to 9.59	-0.25 Percentage change Interval -8.18 to 7.68	0.48 Percentage change Interval -3.44 to 4.4	3.03 Percentage change Interval -0.89 to 6.94
Percent Change From Baseline in Blood Plasma Creatinine Day 7, 12 hrs post dose	8.03 Percentage change Interval -3.02 to 19.07	8.34 Percentage change Interval -2.79 to 19.48	9.33 Percentage change Interval 4.43 to 14.24	4.55 Percentage change Interval -0.35 to 9.46

SECONDARY outcome

Timeframe: 0, 2, 4 and 6 hours post dose on day 1; 0, 2, 4 and 6 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

GFR was used as a measure of renal function.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Glomerular Filtration Rate (GFR) Over Time Day 1, 0 hour	76.4 mL/min Standard Deviation 43.27	92.5 mL/min Standard Deviation 97.37	87.6 mL/min Standard Deviation 64.27	99.2 mL/min Standard Deviation 66.36
Glomerular Filtration Rate (GFR) Over Time Day 1, 2 hours post dose	115.7 mL/min Standard Deviation 57.89	83.3 mL/min Standard Deviation 46.57	112.1 mL/min Standard Deviation 63.30	96.0 mL/min Standard Deviation 44.23
Glomerular Filtration Rate (GFR) Over Time Day 1, 4 hours post dose	117.4 mL/min Standard Deviation 75.09	70.9 mL/min Standard Deviation 36.64	125.4 mL/min Standard Deviation 95.33	101.8 mL/min Standard Deviation 65.34
Glomerular Filtration Rate (GFR) Over Time Day 1, 6 hours post dose	120.2 mL/min Standard Deviation 68.73	71.7 mL/min Standard Deviation 37.27	148.4 mL/min Standard Deviation 138.66	123.0 mL/min Standard Deviation 60.62
Glomerular Filtration Rate (GFR) Over Time Day 7, 0 hour	93.7 mL/min Standard Deviation 75.98	87.8 mL/min Standard Deviation 57.47	96.8 mL/min Standard Deviation 78.65	83.2 mL/min Standard Deviation 53.11
Glomerular Filtration Rate (GFR) Over Time Day 7, 2 hours post dose	95.9 mL/min Standard Deviation 39.47	83.1 mL/min Standard Deviation 35.65	133.5 mL/min Standard Deviation 67.82	91.4 mL/min Standard Deviation 50.57
Glomerular Filtration Rate (GFR) Over Time Day 7, 4 hours post dose	89.6 mL/min Standard Deviation 52.23	94.6 mL/min Standard Deviation 53.43	151.7 mL/min Standard Deviation 109.91	111.3 mL/min Standard Deviation 59.41
Glomerular Filtration Rate (GFR) Over Time Day 7, 6 hours post dose	86.9 mL/min Standard Deviation 49.26	126.6 mL/min Standard Deviation 79.95	111.5 mL/min Standard Deviation 66.30	165.2 mL/min Standard Deviation 228.97

SECONDARY outcome

Timeframe: 0, 2, 4 and 6 hours post dose on day 1; 0, 2, 4 and 6 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

RBF was used as a measure of renal function.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Renal Blood Flow (RBF) Over Time Day 1, 0 hour	398.1 mL/min Standard Deviation 221.24	305.7 mL/min Standard Deviation 159.44	774.7 mL/min Standard Deviation 893.23	737.0 mL/min Standard Deviation 323.14
Renal Blood Flow (RBF) Over Time Day 1, 2 hours post dose	361.3 mL/min Standard Deviation 171.80	357.4 mL/min Standard Deviation 218.28	570.5 mL/min Standard Deviation 212.67	541.7 mL/min Standard Deviation 179.20
Renal Blood Flow (RBF) Over Time Day 1, 4 hours post dose	340.1 mL/min Standard Deviation 169.87	297.4 mL/min Standard Deviation 219.83	700.0 mL/min Standard Deviation 408.73	573.4 mL/min Standard Deviation 287.14
Renal Blood Flow (RBF) Over Time Day 1, 6 hours post dose	465.2 mL/min Standard Deviation 276.84	290.05 mL/min Standard Deviation 138.30	1165.2 mL/min Standard Deviation 912.25	758.7 mL/min Standard Deviation 375.11
Renal Blood Flow (RBF) Over Time Day 7, 0 hour	354.9 mL/min Standard Deviation 223.49	417.0 mL/min Standard Deviation 254.35	548.5 mL/min Standard Deviation 389.77	549.3 mL/min Standard Deviation 247.41
Renal Blood Flow (RBF) Over Time Day 7, 2 hours	331.9 mL/min Standard Deviation 180.59	341.1 mL/min Standard Deviation 156.86	630.4 mL/min Standard Deviation 239.55	659.1 mL/min Standard Deviation 426.18
Renal Blood Flow (RBF) Over Time Day 7, 4 hours	324.2 mL/min Standard Deviation 168.10	285.9 mL/min Standard Deviation 150.82	653.2 mL/min Standard Deviation 412.91	606.3 mL/min Standard Deviation 224.57
Renal Blood Flow (RBF) Over Time Day 7, 6 hours	331.0 mL/min Standard Deviation 228.38	440.8 mL/min Standard Deviation 310.64	667.6 mL/min Standard Deviation 308.52	977.9 mL/min Standard Deviation 975.25

SECONDARY outcome

Timeframe: 0, 0.5, 1, 2, 4, 8 and 12 hours post dose on day 1; day 2; 0, 0.5, 1, 2, 4, 8 and 12 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

Systolic blood pressure measurements were taken.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Supine Systolic Blood Pressure Day 1, 12.0 hours post dose	111.1 mmHg Standard Deviation 14.75	114.8 mmHg Standard Deviation 17.85	127.4 mmHg Standard Deviation 13.92	134.1 mmHg Standard Deviation 14.64
Supine Systolic Blood Pressure Day 2	115.8 mmHg Standard Deviation 9.61	120.9 mmHg Standard Deviation 18.05	125.4 mmHg Standard Deviation 12.66	128.9 mmHg Standard Deviation 13.99
Supine Systolic Blood Pressure Day 7, 0.0 hour	110.5 mmHg Standard Deviation 10.03	115.9 mmHg Standard Deviation 15.47	128.9 mmHg Standard Deviation 14.83	128.8 mmHg Standard Deviation 13.76
Supine Systolic Blood Pressure Day 7, 0.5 hour post dose	116.2 mmHg Standard Deviation 10.93	122.9 mmHg Standard Deviation 11.78	127.4 mmHg Standard Deviation 16.26	130.9 mmHg Standard Deviation 15.06
Supine Systolic Blood Pressure Day 7, 1.0 hour post dose	117.9 mmHg Standard Deviation 10.01	124.8 mmHg Standard Deviation 12.43	127.4 mmHg Standard Deviation 17.46	130.9 mmHg Standard Deviation 15.47
Supine Systolic Blood Pressure Day 7, 2.0 hours post dose	119.3 mmHg Standard Deviation 12.70	127.5 mmHg Standard Deviation 11.95	128.6 mmHg Standard Deviation 19.35	140.7 mmHg Standard Deviation 15.89
Supine Systolic Blood Pressure Day 7, 4.0 hours post dose	120.6 mmHg Standard Deviation 11.71	128.9 mmHg Standard Deviation 13.13	130.5 mmHg Standard Deviation 18.15	134.9 mmHg Standard Deviation 13.20
Supine Systolic Blood Pressure Day 7, 8.0 hours post dose	111.3 mmHg Standard Deviation 12.52	119.3 mmHg Standard Deviation 10.44	123.1 mmHg Standard Deviation 12.72	130.0 mmHg Standard Deviation 15.88
Supine Systolic Blood Pressure Day 7, 12.0 hours post dose	107.9 mmHg Standard Deviation 16.70	116.5 mmHg Standard Deviation 14.85	120.3 mmHg Standard Deviation 12.60	131.9 mmHg Standard Deviation 18.71
Supine Systolic Blood Pressure Day 1, 0.0 hour	114.8 mmHg Standard Deviation 14.10	127.0 mmHg Standard Deviation 16.62	136.1 mmHg Standard Deviation 18.80	133.2 mmHg Standard Deviation 14.79
Supine Systolic Blood Pressure Day 1, 0.5 hour post dose	122.8 mmHg Standard Deviation 14.36	121.5 mmHg Standard Deviation 21.78	132.9 mmHg Standard Deviation 19.52	132.5 mmHg Standard Deviation 17.85
Supine Systolic Blood Pressure Day 1, 1.0 hour post dose	123.9 mmHg Standard Deviation 16.53	122.2 mmHg Standard Deviation 19.20	134.1 mmHg Standard Deviation 18.57	133.2 mmHg Standard Deviation 15.22
Supine Systolic Blood Pressure Day 1, 2.0 hours post dose	125.4 mmHg Standard Deviation 13.68	127.2 mmHg Standard Deviation 16.71	134.2 mmHg Standard Deviation 19.85	132.6 mmHg Standard Deviation 17.47
Supine Systolic Blood Pressure Day 1, 4.0 hours post dose	133.1 mmHg Standard Deviation 18.65	130.3 mmHg Standard Deviation 17.14	140.7 mmHg Standard Deviation 20.67	142.1 mmHg Standard Deviation 17.93
Supine Systolic Blood Pressure Day 1, 8.0 hours post dose	113.6 mmHg Standard Deviation 13.29	120.9 mmHg Standard Deviation 16.85	127.3 mmHg Standard Deviation 17.39	132.2 mmHg Standard Deviation 11.40

SECONDARY outcome

Timeframe: 0, 0.5, 1, 2, 4, 8 and 12 hours post dose on day 1; day 2; 0, 0.5, 1, 2, 4, 8 and 12 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

Diastolic blood pressure measurements were taken.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Supine Diastolic Blood Pressure Day 1, 0.0 hour	68.2 mmHg Standard Deviation 9.85	74.1 mmHg Standard Deviation 13.20	77.6 mmHg Standard Deviation 10.57	74.9 mmHg Standard Deviation 9.99
Supine Diastolic Blood Pressure Day 1, 0.5 hour post dose	71.2 mmHg Standard Deviation 12.00	75.5 mmHg Standard Deviation 13.77	76.3 mmHg Standard Deviation 11.85	75.8 mmHg Standard Deviation 10.67
Supine Diastolic Blood Pressure Day 1, 1.0 hour post dose	71.3 mmHg Standard Deviation 12.00	75.8 mmHg Standard Deviation 13.73	75.3 mmHg Standard Deviation 10.37	76.2 mmHg Standard Deviation 9.59
Supine Diastolic Blood Pressure Day 1, 2.0 hours post dose	73.3 mmHg Standard Deviation 12.01	77.1 mmHg Standard Deviation 10.61	77.6 mmHg Standard Deviation 11.79	76.0 mmHg Standard Deviation 10.78
Supine Diastolic Blood Pressure Day 1, 4.0 hours post dose	75.6 mmHg Standard Deviation 13.77	79.1 mmHg Standard Deviation 12.21	80.0 mmHg Standard Deviation 13.60	79.9 mmHg Standard Deviation 9.08
Supine Diastolic Blood Pressure Day 1, 8.0 hours post dose	68.5 mmHg Standard Deviation 11.15	70.4 mmHg Standard Deviation 11.12	75.2 mmHg Standard Deviation 10.23	76.2 mmHg Standard Deviation 8.89
Supine Diastolic Blood Pressure Day 1, 12.0 hours post dose	65.4 mmHg Standard Deviation 11.49	71.7 mmHg Standard Deviation 13.43	75.5 mmHg Standard Deviation 8.33	75.7 mmHg Standard Deviation 8.81
Supine Diastolic Blood Pressure Day 2	71.6 mmHg Standard Deviation 10.03	74.9 mmHg Standard Deviation 13.33	73.2 mmHg Standard Deviation 10.78	75.1 mmHg Standard Deviation 8.35
Supine Diastolic Blood Pressure Day 7, 0.0 hour	66.9 mmHg Standard Deviation 11.04	68.4 mmHg Standard Deviation 11.37	74.7 mmHg Standard Deviation 8.77	74.7 mmHg Standard Deviation 9.62
Supine Diastolic Blood Pressure Day 7, 0.5 hour post dose	69.6 mmHg Standard Deviation 11.74	73.9 mmHg Standard Deviation 9.48	74.3 mmHg Standard Deviation 9.36	74.5 mmHg Standard Deviation 9.65
Supine Diastolic Blood Pressure Day 7, 1.0 hour post dose	69.3 mmHg Standard Deviation 10.49	73.9 mmHg Standard Deviation 8.94	73.5 mmHg Standard Deviation 8.52	75.1 mmHg Standard Deviation 8.71
Supine Diastolic Blood Pressure Day 7, 2.0 hours post dose	70.6 mmHg Standard Deviation 11.85	76.7 mmHg Standard Deviation 9.15	72.0 mmHg Standard Deviation 8.20	78.8 mmHg Standard Deviation 9.29
Supine Diastolic Blood Pressure Day 7, 4.0 hours post dose	69.6 mmHg Standard Deviation 11.17	74.5 mmHg Standard Deviation 10.86	74.4 mmHg Standard Deviation 9.60	78.4 mmHg Standard Deviation 9.77
Supine Diastolic Blood Pressure Day 7, 8.0 hours post dose	69.3 mmHg Standard Deviation 10.08	71.5 mmHg Standard Deviation 8.43	71.4 mmHg Standard Deviation 7.84	75.3 mmHg Standard Deviation 8.50
Supine Diastolic Blood Pressure Day 7, 12.0 hours post dose	65.3 mmHg Standard Deviation 10.95	69.8 mmHg Standard Deviation 12.39	70.7 mmHg Standard Deviation 8.36	75.7 mmHg Standard Deviation 11.47

SECONDARY outcome

Timeframe: 0, 0.5, 1, 2, 4, 8 and 12 hours post dose on day 1; day 2; 0, 0.5, 1, 2, 4, 8 and 12 hours post dose on day 7

Population: The Pharmacodynamic (PD) analysis set, which included all participants who had no major protocol deviation with impact on PD data, were included in the analysis.

Pulse rate measurements were taken.

Outcome measures

Outcome measures
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=16 Participants Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=16 Participants Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 Participants Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Supine Pulse Rate Day 1, 0.0 hour	56.8 BPM Standard Deviation 8.89	61.7 BPM Standard Deviation 14.30	65.7 BPM Standard Deviation 9.26	65.5 BPM Standard Deviation 8.44
Supine Pulse Rate Day 1, 0.5 hour post dose	61.3 BPM Standard Deviation 9.34	60.7 BPM Standard Deviation 10.45	64.1 BPM Standard Deviation 8.59	63.4 BPM Standard Deviation 9.29
Supine Pulse Rate Day 1, 1.0 hour post dose	62.4 BPM Standard Deviation 8.97	62.7 BPM Standard Deviation 10.19	64.2 BPM Standard Deviation 7.49	64.0 BPM Standard Deviation 10.39
Supine Pulse Rate Day 1, 2.0 hours post dose	61.0 BPM Standard Deviation 9.02	64.3 BPM Standard Deviation 12.39	65.6 BPM Standard Deviation 8.28	63.2 BPM Standard Deviation 8.89
Supine Pulse Rate Day 1, 4.0 hours post dose	60.0 BPM Standard Deviation 8.51	62.9 BPM Standard Deviation 13.29	64.0 BPM Standard Deviation 6.51	65.3 BPM Standard Deviation 9.65
Supine Pulse Rate Day 1, 8.0 hours post dose	67.6 BPM Standard Deviation 11.70	69.1 BPM Standard Deviation 11.34	73.9 BPM Standard Deviation 10.20	67.5 BPM Standard Deviation 10.09
Supine Pulse Rate Day 1, 12.0 hours post dose	61.1 BPM Standard Deviation 13.36	62.8 BPM Standard Deviation 10.83	73.7 BPM Standard Deviation 13.52	65.4 BPM Standard Deviation 9.68
Supine Pulse Rate Day 2	60.1 BPM Standard Deviation 12.18	64.5 BPM Standard Deviation 11.95	71.3 BPM Standard Deviation 10.58	66.5 BPM Standard Deviation 9.20
Supine Pulse Rate Day 7, 0.0 hour post dose	63.0 BPM Standard Deviation 11.97	60.6 BPM Standard Deviation 12.69	62.9 BPM Standard Deviation 5.54	62.8 BPM Standard Deviation 8.16
Supine Pulse Rate Day 7, 0.5 hour post dose	65.0 BPM Standard Deviation 12.63	60.1 BPM Standard Deviation 12.07	63.0 BPM Standard Deviation 4.36	61.8 BPM Standard Deviation 9.35
Supine Pulse Rate Day 7, 1.0 hour post dose	63.3 BPM Standard Deviation 13.21	61.6 BPM Standard Deviation 11.70	62.3 BPM Standard Deviation 5.87	61.6 BPM Standard Deviation 7.70
Supine Pulse Rate Day 7, 2.0 hours post dose	63.9 BPM Standard Deviation 10.42	58.7 BPM Standard Deviation 11.49	61.2 BPM Standard Deviation 6.17	63.6 BPM Standard Deviation 9.16
Supine Pulse Rate Day 7, 4.0 hours post dose	65.7 BPM Standard Deviation 10.85	60.7 BPM Standard Deviation 11.34	62.9 BPM Standard Deviation 6.45	62.7 BPM Standard Deviation 9.20
Supine Pulse Rate Day 7, 8.0 hours post dose	67.1 BPM Standard Deviation 10.20	66.5 BPM Standard Deviation 11.80	66.3 BPM Standard Deviation 7.34	64.8 BPM Standard Deviation 10.83
Supine Pulse Rate Day 7, 12.0 hours post dose	66.7 BPM Standard Deviation 13.28	71.9 BPM Standard Deviation 17.30	66.2 BPM Standard Deviation 6.97	67.1 BPM Standard Deviation 11.10

Adverse Events

LCZ696 - Heart Failure (HF) Cohort

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Valsartan - HF Cohort

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

LCZ696 - Hypertension (HTN) Cohort

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Valsartan - HTN Cohort

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	LCZ696 - Heart Failure (HF) Cohort n=16 participants at risk Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2.	Valsartan - HF Cohort n=15 participants at risk Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2.	LCZ696 - Hypertension (HTN) Cohort n=15 participants at risk Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2.	Valsartan - HTN Cohort n=16 participants at risk Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/16	0.00% 0/15	0.00% 0/15	6.2% 1/16
Gastrointestinal disorders Toothache	0.00% 0/16	0.00% 0/15	6.7% 1/15	0.00% 0/16
Infections and infestations Nasopharyngitis	6.2% 1/16	0.00% 0/15	0.00% 0/15	0.00% 0/16
Investigations Blood creatinine increased	6.2% 1/16	6.7% 1/15	0.00% 0/15	0.00% 0/16
Nervous system disorders Dizziness	6.2% 1/16	0.00% 0/15	0.00% 0/15	0.00% 0/16
Nervous system disorders Headache	0.00% 0/16	0.00% 0/15	0.00% 0/15	6.2% 1/16
Nervous system disorders Presyncope	6.2% 1/16	0.00% 0/15	0.00% 0/15	0.00% 0/16
Renal and urinary disorders Dysuria	0.00% 0/16	0.00% 0/15	0.00% 0/15	6.2% 1/16

Additional Information

Study Director

Novartis

Phone: 862-778-1873

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER