Sodium Excretion of LCZ696 in Patients With Hypertension; Heart Failure and Healthy Volunteers
Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01353508
Collaborator
(none)
32
1
4
17.1
1.9
Study Details
Study Description
Brief Summary
Assess mechanism of action of LCZ696 related to sodium excretion.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
32 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-blind, Controlled, Crossover Study to Evaluate the Sodium Excretion of LCZ696 in Patients With Stable Heart Failure, in Patients With Hypertension, and in Healthy Volunteers
Study Start Date
:
Mar 1, 2011
Actual Primary Completion Date
:
Aug 1, 2012
Actual Study Completion Date
:
Aug 1, 2012
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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. |
Drug: LCZ696
200 mg and 400 mg tablets
Drug: Valsartan
160 mg tablets
|
| Experimental: 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. |
Drug: LCZ696
200 mg and 400 mg tablets
Drug: Valsartan
160 mg tablets
|
| Experimental: 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. |
Drug: LCZ696
200 mg and 400 mg tablets
Drug: Valsartan
160 mg tablets
|
| Experimental: 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. |
Drug: LCZ696
200 mg and 400 mg tablets
Drug: Valsartan
160 mg tablets
|
Outcome Measures
Primary Outcome Measures
- 24-hour Urinary Sodium Excretion [day 1]
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).
- Cumulative 7-day Urinary Sodium Excretion [7 day-cummulative (days 1 through 7)]
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).
Secondary Outcome Measures
- 24-hour Diuresis [day 1]
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.
- 7-day Cumulative Diuresis [7-day cumulative (days 1 through 7)]
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.
- Urinary Cyclic Guanosine Monophosphate (cGMP) Excretion Over 24 Hours [day 1, day 6, day 7]
cGMP was analyzed at a central laboratory. The measure type used for this OM was Geometric LSM.
- Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker [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]
MR-proANP was analyzed at a central laboratory.
- Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker [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]
BNP was analyzed at a central laboratory.
- Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker [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]
MR-proADM was analyzed at a central laboratory.
- Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker [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.
- Percent Change From Baseline in C-terminal-proendothelin-1 (CT-proET-1) Biomarker [12 hours post dose on day 1; 24 hours post dose on day 2; 0 and 12 hours post dose on day 7]
CT-proET-1 was analyzed at a central laboratory.
- Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker [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]
NT-proBNP was analyzed at a central laboratory.
- Percent Change From Baseline in Aldosterone Biomarker [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]
Aldosterone was analyzed at a central laboratory.
- Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) [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]
Urine was collected in 12-hour intervals, and of each pooled 24-hour (daily) sample, sodium, potassium, albumin and calcium were measured.
- Percent Change From Baseline in Blood Plasma Creatinine [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]
Blood plasma creatinine was analyzed at a central laboratory.
- Glomerular Filtration Rate (GFR) Over Time [0, 2, 4 and 6 hours post dose on day 1; 0, 2, 4 and 6 hours post dose on day 7]
GFR was used as a measure of renal function.
- Renal Blood Flow (RBF) Over Time [0, 2, 4 and 6 hours post dose on day 1; 0, 2, 4 and 6 hours post dose on day 7]
RBF was used as a measure of renal function.
- Supine Systolic Blood Pressure [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]
Systolic blood pressure measurements were taken.
- Supine Diastolic Blood Pressure [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]
Diastolic blood pressure measurements were taken.
- Supine Pulse Rate [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]
Pulse rate measurements were taken.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Patients with heart failure: documented NYHA class II-III heart failure
-
Patients with hypertension: stable hypertensive medication for the preceding 2 months
Exclusion Criteria:
-
Women of childbearing potential
-
History of recent myocardial infarction
-
History of dialysis or renal transplant
-
Patients with type 1 diabetes mellitus
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Novartis Investigative Site | Moscow | Russian Federation | 117198 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01353508
Other Study ID Numbers:
- CLCZ696B2223
First Posted:
May 13, 2011
Last Update Posted:
Nov 23, 2015
Last Verified:
Oct 1, 2015
Keywords provided by Novartis Pharmaceuticals
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | 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. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | LCZ696 to Valsartan - Heart Failure (HF) Cohort | Valsartan to LCZ696 - HF Cohort | LCZ696 to Valsartan - Hypertension (HTN) Cohort | Valsartan to LCZ696 - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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 Title: Period 1 - First Intervention (7 Days) | ||||
| STARTED | 8 | 8 | 8 | 8 |
| COMPLETED | 8 | 8 | 8 | 7 |
| NOT COMPLETED | 0 | 0 | 0 | 1 |
| Period Title: Period 1 - First Intervention (7 Days) | ||||
| STARTED | 8 | 8 | 8 | 7 |
| COMPLETED | 7 | 8 | 8 | 7 |
| NOT COMPLETED | 1 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | LCZ696 to Valsartan - Heart Failure (HF) Cohort | Valsartan to LCZ696 - HF Cohort | LCZ696 to Valsartan - Hypertension (HTN) Cohort | Valsartan to LCZ696 - HTN Cohort | Total |
|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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 of all reporting groups |
| Overall Participants | 8 | 8 | 8 | 8 | 32 |
| Age (Years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [Years] |
63.3
(10.15)
|
67.6
(9.07)
|
58.0
(8.02)
|
61.6
(8.40)
|
62.6
(8.86)
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
2
25%
|
0
0%
|
5
62.5%
|
2
25%
|
9
28.1%
|
| Male |
6
75%
|
8
100%
|
3
37.5%
|
6
75%
|
23
71.9%
|
Outcome Measures
| Title | 24-hour Urinary Sodium Excretion |
|---|---|
| Description | 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). |
| Time Frame | day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Least Squares Mean (95% Confidence Interval) [mmol/24 hours] |
220.58
|
198.73
|
177.40
|
146.18
|
| Title | Cumulative 7-day Urinary Sodium Excretion |
|---|---|
| Description | 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). |
| Time Frame | 7 day-cummulative (days 1 through 7) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Least Squares Mean (95% Confidence Interval) [mmol/7 days] |
1020.57
|
1114.18
|
906.81
|
943.26
|
| Title | 24-hour Diuresis |
|---|---|
| Description | 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. |
| Time Frame | day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Least Squares Mean (95% Confidence Interval) [mL/24 hours] |
3199.37
|
2874.36
|
3382.94
|
2393.61
|
| Title | 7-day Cumulative Diuresis |
|---|---|
| Description | 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. |
| Time Frame | 7-day cumulative (days 1 through 7) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Least Squares Mean (95% Confidence Interval) [mL] |
12347.92
|
13180.02
|
16980.05
|
15265.35
|
| Title | Urinary Cyclic Guanosine Monophosphate (cGMP) Excretion Over 24 Hours |
|---|---|
| Description | cGMP was analyzed at a central laboratory. The measure type used for this OM was Geometric LSM. |
| Time Frame | day 1, day 6, day 7 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1 |
1851.79
|
884.99
|
1085.76
|
557.53
|
| Day 6 |
1467.67
|
865.62
|
863.32
|
562.11
|
| Day 7 |
1571.02
|
859.07
|
1107.04
|
603.90
|
| Title | Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker |
|---|---|
| Description | MR-proANP was analyzed at a central laboratory. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 2.0 hours post dose |
-7.04
|
2.08
|
-10.11
|
-1.66
|
| Day 1, 4.0 hrs post dose |
-17.39
|
-6.74
|
-12.68
|
-7.33
|
| Day 1, 6.0 hours post dose |
-23.99
|
-10.16
|
-17.82
|
-4.52
|
| Day 1, 12.0 hrs post dose |
-27.58
|
-7.48
|
-19.77
|
-15.20
|
| Day 2, 24.0 hrs post dose |
-25.13
|
-14.53
|
-17.30
|
-9.45
|
| Day 7, 0.0 hours |
-21.27
|
-2.54
|
-16.03
|
0.44
|
| Day 7, 4.0 hours post dose |
-24.35
|
1.64
|
-19.34
|
-2.56
|
| Day 7, 6.0 hours post dose |
-23.40
|
-3.53
|
-20.84
|
-1.98
|
| Day 7, 12.0 hours post dose |
-20.95
|
-12.65
|
-23.09
|
-10.27
|
| Title | Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker |
|---|---|
| Description | BNP was analyzed at a central laboratory. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 0.5 hour post dose |
72.32
|
-8.93
|
-10.75
|
-5.94
|
| Day 1, 1.0 hr post dose |
121.85
|
-0.83
|
1218.56
|
-33.19
|
| Day 1, 2.0 hours post dose |
176.35
|
21.92
|
31.10
|
-0.38
|
| Day 1, 4.0 hrs post dose |
50.12
|
-1.78
|
38.82
|
11.06
|
| Day 1, 6.0 hrs post dose |
130.62
|
11.09
|
68.23
|
7.97
|
| Day 1, 12.0 hrs post dose |
90.58
|
30.07
|
85.93
|
8.51
|
| Day 2, 24 hrs post dose |
102.88
|
5.18
|
-0.66
|
-20.61
|
| Day 7, 0.0 hr |
190.96
|
27.75
|
14.20
|
-7.19
|
| Day 7, 4.0 hrs post dose |
220.38
|
34.44
|
34.92
|
5.20
|
| Day 7, 6.0 hrs post dose |
195.06
|
46.75
|
7.78
|
7.82
|
| Day 7, 12.0 hrs post dose |
236.05
|
70.31
|
38.45
|
25.79
|
| Title | Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker |
|---|---|
| Description | MR-proADM was analyzed at a central laboratory. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 16 | 16 |
| Day 1, 2.0 hours post dose |
8.04
|
-2.87
|
| Day 1, 4.0 hrs post dose |
21.22
|
-8.22
|
| Day 1, 6.0 hrs post dose |
20.18
|
-8.81
|
| Day 1, 12.0 hrs post dose |
40.70
|
7.61
|
| Day 2, 24 hrs post dose |
57.28
|
0.72
|
| Day 7, 0.0 hrs |
61.28
|
1.38
|
| Day 7, 4.0 hrs post dose |
51.71
|
-5.27
|
| Day 7, 6.0 hrs post dose |
48.22
|
-3.63
|
| Day 7, 12.0 hrs post dose |
69.45
|
2.15
|
| Title | Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker |
|---|---|
| Description | ProCNP was analyzed at a central laboratory. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 16 | 16 |
| Day 1, 2.0 hrs post dose |
0.35
|
-1.01
|
| Day 1, 4.0 hours post dose |
34.58
|
-6.02
|
| Day 1, 6.0 hrs post dose |
67.85
|
-16.19
|
| Day 1, 8.0 hrs post dose |
123.75
|
-9.87
|
| Day 1, 12.0 hrs post dose |
190.36
|
15.55
|
| Day 2, 24 hrs post dose |
218.81
|
4.99
|
| Day 7, 0.0 hour |
244.20
|
0.09
|
| Day 7, 4.0 hours post dose |
216.61
|
-8.94
|
| Day 7, 6.0 hrs post dose |
211.21
|
-18.17
|
| Day 7, 8.0 hrs post dose |
241.99
|
-11.30
|
| Day 7, 12.0 hrs post dose |
278.58
|
0.88
|
| Title | Percent Change From Baseline in C-terminal-proendothelin-1 (CT-proET-1) Biomarker |
|---|---|
| Description | CT-proET-1 was analyzed at a central laboratory. |
| Time Frame | 12 hours post dose on day 1; 24 hours post dose on day 2; 0 and 12 hours post dose on day 7 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 12.0 hours post dose |
36.39
|
2.51
|
108.87
|
54.07
|
| Day 2, 24.0 hours post dose |
32.44
|
11.41
|
123.45
|
38.70
|
| Day 7, 0.0 hour |
31.98
|
0.62
|
94.76
|
41.77
|
| Day 7, 12.0 hours post dose |
41.75
|
7.05
|
117.84
|
61.90
|
| Title | Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker |
|---|---|
| Description | NT-proBNP was analyzed at a central laboratory. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 2.0 hours post dose |
3.06
|
6.87
|
5.10
|
8.32
|
| Day 1, 4.0 hours post dose |
2.68
|
13.21
|
44.79
|
22.14
|
| Day 1, 6.0 hours post dose |
3.71
|
21.70
|
12.58
|
21.21
|
| Day 1, 12.0 hours post dose |
17.15
|
42.32
|
61.46
|
33.17
|
| Day 2, 24 hours post dose |
-21.85
|
23.51
|
8.61
|
-4.41
|
| Day 7, 0.0 hour |
-19.57
|
2.29
|
-10.14
|
-0.13
|
| Day 7, 4.0 hours post dose |
-14.60
|
14.85
|
-8.10
|
19.83
|
| Day 7, 6.0 hours post dose |
-15.05
|
17.34
|
-9.42
|
20.47
|
| Day 7, 12.0 hours post dose |
1.37
|
46.05
|
12.22
|
47.27
|
| Title | Percent Change From Baseline in Aldosterone Biomarker |
|---|---|
| Description | Aldosterone was analyzed at a central laboratory. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 6.0 hours post dose |
71.15
|
-14.63
|
90.51
|
72.92
|
| Day 1, 12.0 hours post dose |
208.06
|
8.36
|
249.13
|
325.31
|
| Day 2, 24.0 hours post dose |
168.32
|
71.73
|
438.28
|
524.93
|
| Day 7, 0.0 hour |
111.21
|
21.68
|
49.91
|
5.61
|
| Day 7, 6.0 hours post dose |
65.22
|
24.58
|
24.47
|
107.60
|
| Day 7, 12.0 hours post dose |
238.32
|
230.06
|
147.89
|
152.37
|
| Title | Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) |
|---|---|
| Description | Urine was collected in 12-hour intervals, and of each pooled 24-hour (daily) sample, sodium, potassium, albumin and calcium were measured. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Calcium, day 1, 2.0 hours post dose |
-0.05
|
-1.40
|
0.51
|
0.08
|
| Calcium, day 1, 4.0 hours post dose |
-2.19
|
-2.46
|
0.76
|
0.27
|
| Calcium, day 1, 6.0 hours post dose |
-3.69
|
-4.03
|
-2.22
|
-2.49
|
| Calcium, day 1, 12.0 hours post dose |
-2.80
|
-1.34
|
1.77
|
0.82
|
| Calcium, day 2, 24 hours post dose |
-2.09
|
0.44
|
2.06
|
1.34
|
| Calcium, day 7, 0.0 hour |
-0.34
|
-1.11
|
-5.82
|
-6.19
|
| Calcium, day 7, 4.0 hours post dose |
-2.45
|
-2.17
|
-8.46
|
-7.42
|
| Calcium, day 7, 6.0 hours post dose |
-4.30
|
-3.53
|
-9.12
|
-9.89
|
| Calcium, day 7, 12.0 hours post dose |
-3.41
|
-1.27
|
-4.63
|
-4.99
|
| Chloride, day 1, 2.0 hours post dose |
-0.33
|
-0.47
|
-0.35
|
0.22
|
| Chloride, day 1, 4.0 hours post dose |
-1.35
|
-0.61
|
0.05
|
0.41
|
| Chloride, day 1, 6.0 hours post dose |
-0.66
|
-0.42
|
-0.48
|
0.05
|
| Chloride, day 1, 12.0 hours post dose |
0.46
|
1.44
|
-0.93
|
-0.15
|
| Chloride, day 2, 24 hours post dose |
0.49
|
0.73
|
0.11
|
0.58
|
| Chloride, day 7, 0.0 hour |
1.46
|
1.28
|
0.89
|
0.63
|
| Chloride, day 7, 4.0 hours post dose |
0.47
|
0.22
|
-0.05
|
0.28
|
| Chloride, day 7, 6.0 hours post dose |
0.87
|
1.32
|
-0.21
|
-0.86
|
| Chloride, day 7, 12.0 hours post dose |
0.98
|
1.20
|
-1.16
|
-1.48
|
| Potassium, day 1, 2.0 hours post dose |
1.96
|
-1.25
|
-1.20
|
1.69
|
| Potassium, day 1, 4.0 hours post dose |
-0.16
|
-0.11
|
0.42
|
1.11
|
| Potassium, day 1, 6.0 hours post dose |
-2.91
|
-5.88
|
-0.63
|
-2.61
|
| Potassium, day 1, 12.0 hours post dose |
6.63
|
15.27
|
18.57
|
19.96
|
| Potassium, day 2, 24.0 hours post dose |
2.06
|
0.14
|
7.70
|
7.00
|
| Potassium, day 7, 0.0 hour |
1.06
|
-1.55
|
-0.47
|
1.29
|
| Potassium, day 7, 4.0 hours post dose |
-2.16
|
-2.93
|
3.61
|
0.28
|
| Potassium, day 7, 6.0 hours post dose |
-3.23
|
-5.16
|
-4.20
|
-4.14
|
| Potassium, day 7, 12.0 hours post dose |
17.22
|
12.32
|
18.19
|
19.28
|
| Sodium, day 1, 2.0 hours post dose |
-1.09
|
-0.67
|
-0.63
|
-0.17
|
| Sodium, day 1, 4.0 hours post dose |
-1.82
|
-1.18
|
-0.18
|
-0.04
|
| Sodium, day 1, 6.0 hours post dose |
-1.47
|
-1.12
|
-0.62
|
-0.17
|
| Sodium, day 1, 12.0 hours post dose |
-0.17
|
0.48
|
-0.12
|
0.14
|
| Sodium, day 2, 24.0 hours post dose |
0.03
|
1.06
|
0.85
|
1.24
|
| Sodium, day 7, 0.0 hour |
1.21
|
1.36
|
0.69
|
0.84
|
| Sodium, day 7, 4.0 hours post dose |
-0.25
|
-0.89
|
-0.81
|
-0.16
|
| Sodium, day 7, 6.0 hours post dose |
0.01
|
-0.19
|
-0.74
|
-0.86
|
| Sodium, day 7, 12.0 hours post dose |
0.34
|
0.78
|
-0.41
|
-1.04
|
| Title | Percent Change From Baseline in Blood Plasma Creatinine |
|---|---|
| Description | Blood plasma creatinine was analyzed at a central laboratory. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 4.0 hours post dose |
-7.06
|
-3.55
|
-7.48
|
-0.91
|
| Day 1, 6.0 hrs post dose |
-2.97
|
-0.07
|
-1.72
|
4.40
|
| Day 1, 12.0 hrs post dose |
3.02
|
5.36
|
6.22
|
9.23
|
| Day 2, 24 hrs post dose |
3.73
|
4.02
|
13.64
|
6.18
|
| Day 7, 0.0 hour |
4.24
|
0.55
|
1.76
|
1.71
|
| Day 7, 4.0 hrs post dose |
-1.47
|
-5.09
|
-3.02
|
-1.28
|
| Day 7, 6.0 hrs post dose |
1.72
|
-0.25
|
0.48
|
3.03
|
| Day 7, 12 hrs post dose |
8.03
|
8.34
|
9.33
|
4.55
|
| Title | Glomerular Filtration Rate (GFR) Over Time |
|---|---|
| Description | GFR was used as a measure of renal function. |
| Time Frame | 0, 2, 4 and 6 hours post dose on day 1; 0, 2, 4 and 6 hours post dose on day 7 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 0 hour |
76.4
(43.27)
|
92.5
(97.37)
|
87.6
(64.27)
|
99.2
(66.36)
|
| Day 1, 2 hours post dose |
115.7
(57.89)
|
83.3
(46.57)
|
112.1
(63.30)
|
96.0
(44.23)
|
| Day 1, 4 hours post dose |
117.4
(75.09)
|
70.9
(36.64)
|
125.4
(95.33)
|
101.8
(65.34)
|
| Day 1, 6 hours post dose |
120.2
(68.73)
|
71.7
(37.27)
|
148.4
(138.66)
|
123.0
(60.62)
|
| Day 7, 0 hour |
93.7
(75.98)
|
87.8
(57.47)
|
96.8
(78.65)
|
83.2
(53.11)
|
| Day 7, 2 hours post dose |
95.9
(39.47)
|
83.1
(35.65)
|
133.5
(67.82)
|
91.4
(50.57)
|
| Day 7, 4 hours post dose |
89.6
(52.23)
|
94.6
(53.43)
|
151.7
(109.91)
|
111.3
(59.41)
|
| Day 7, 6 hours post dose |
86.9
(49.26)
|
126.6
(79.95)
|
111.5
(66.30)
|
165.2
(228.97)
|
| Title | Renal Blood Flow (RBF) Over Time |
|---|---|
| Description | RBF was used as a measure of renal function. |
| Time Frame | 0, 2, 4 and 6 hours post dose on day 1; 0, 2, 4 and 6 hours post dose on day 7 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 0 hour |
398.1
(221.24)
|
305.7
(159.44)
|
774.7
(893.23)
|
737.0
(323.14)
|
| Day 1, 2 hours post dose |
361.3
(171.80)
|
357.4
(218.28)
|
570.5
(212.67)
|
541.7
(179.20)
|
| Day 1, 4 hours post dose |
340.1
(169.87)
|
297.4
(219.83)
|
700.0
(408.73)
|
573.4
(287.14)
|
| Day 1, 6 hours post dose |
465.2
(276.84)
|
290.05
(138.30)
|
1165.2
(912.25)
|
758.7
(375.11)
|
| Day 7, 0 hour |
354.9
(223.49)
|
417.0
(254.35)
|
548.5
(389.77)
|
549.3
(247.41)
|
| Day 7, 2 hours |
331.9
(180.59)
|
341.1
(156.86)
|
630.4
(239.55)
|
659.1
(426.18)
|
| Day 7, 4 hours |
324.2
(168.10)
|
285.9
(150.82)
|
653.2
(412.91)
|
606.3
(224.57)
|
| Day 7, 6 hours |
331.0
(228.38)
|
440.8
(310.64)
|
667.6
(308.52)
|
977.9
(975.25)
|
| Title | Supine Systolic Blood Pressure |
|---|---|
| Description | Systolic blood pressure measurements were taken. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 0.0 hour |
114.8
(14.10)
|
127.0
(16.62)
|
136.1
(18.80)
|
133.2
(14.79)
|
| Day 1, 0.5 hour post dose |
122.8
(14.36)
|
121.5
(21.78)
|
132.9
(19.52)
|
132.5
(17.85)
|
| Day 1, 1.0 hour post dose |
123.9
(16.53)
|
122.2
(19.20)
|
134.1
(18.57)
|
133.2
(15.22)
|
| Day 1, 2.0 hours post dose |
125.4
(13.68)
|
127.2
(16.71)
|
134.2
(19.85)
|
132.6
(17.47)
|
| Day 1, 4.0 hours post dose |
133.1
(18.65)
|
130.3
(17.14)
|
140.7
(20.67)
|
142.1
(17.93)
|
| Day 1, 8.0 hours post dose |
113.6
(13.29)
|
120.9
(16.85)
|
127.3
(17.39)
|
132.2
(11.40)
|
| Day 1, 12.0 hours post dose |
111.1
(14.75)
|
114.8
(17.85)
|
127.4
(13.92)
|
134.1
(14.64)
|
| Day 2 |
115.8
(9.61)
|
120.9
(18.05)
|
125.4
(12.66)
|
128.9
(13.99)
|
| Day 7, 0.0 hour |
110.5
(10.03)
|
115.9
(15.47)
|
128.9
(14.83)
|
128.8
(13.76)
|
| Day 7, 0.5 hour post dose |
116.2
(10.93)
|
122.9
(11.78)
|
127.4
(16.26)
|
130.9
(15.06)
|
| Day 7, 1.0 hour post dose |
117.9
(10.01)
|
124.8
(12.43)
|
127.4
(17.46)
|
130.9
(15.47)
|
| Day 7, 2.0 hours post dose |
119.3
(12.70)
|
127.5
(11.95)
|
128.6
(19.35)
|
140.7
(15.89)
|
| Day 7, 4.0 hours post dose |
120.6
(11.71)
|
128.9
(13.13)
|
130.5
(18.15)
|
134.9
(13.20)
|
| Day 7, 8.0 hours post dose |
111.3
(12.52)
|
119.3
(10.44)
|
123.1
(12.72)
|
130.0
(15.88)
|
| Day 7, 12.0 hours post dose |
107.9
(16.70)
|
116.5
(14.85)
|
120.3
(12.60)
|
131.9
(18.71)
|
| Title | Supine Diastolic Blood Pressure |
|---|---|
| Description | Diastolic blood pressure measurements were taken. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 0.0 hour |
68.2
(9.85)
|
74.1
(13.20)
|
77.6
(10.57)
|
74.9
(9.99)
|
| Day 1, 0.5 hour post dose |
71.2
(12.00)
|
75.5
(13.77)
|
76.3
(11.85)
|
75.8
(10.67)
|
| Day 1, 1.0 hour post dose |
71.3
(12.00)
|
75.8
(13.73)
|
75.3
(10.37)
|
76.2
(9.59)
|
| Day 1, 2.0 hours post dose |
73.3
(12.01)
|
77.1
(10.61)
|
77.6
(11.79)
|
76.0
(10.78)
|
| Day 1, 4.0 hours post dose |
75.6
(13.77)
|
79.1
(12.21)
|
80.0
(13.60)
|
79.9
(9.08)
|
| Day 1, 8.0 hours post dose |
68.5
(11.15)
|
70.4
(11.12)
|
75.2
(10.23)
|
76.2
(8.89)
|
| Day 1, 12.0 hours post dose |
65.4
(11.49)
|
71.7
(13.43)
|
75.5
(8.33)
|
75.7
(8.81)
|
| Day 2 |
71.6
(10.03)
|
74.9
(13.33)
|
73.2
(10.78)
|
75.1
(8.35)
|
| Day 7, 0.0 hour |
66.9
(11.04)
|
68.4
(11.37)
|
74.7
(8.77)
|
74.7
(9.62)
|
| Day 7, 0.5 hour post dose |
69.6
(11.74)
|
73.9
(9.48)
|
74.3
(9.36)
|
74.5
(9.65)
|
| Day 7, 1.0 hour post dose |
69.3
(10.49)
|
73.9
(8.94)
|
73.5
(8.52)
|
75.1
(8.71)
|
| Day 7, 2.0 hours post dose |
70.6
(11.85)
|
76.7
(9.15)
|
72.0
(8.20)
|
78.8
(9.29)
|
| Day 7, 4.0 hours post dose |
69.6
(11.17)
|
74.5
(10.86)
|
74.4
(9.60)
|
78.4
(9.77)
|
| Day 7, 8.0 hours post dose |
69.3
(10.08)
|
71.5
(8.43)
|
71.4
(7.84)
|
75.3
(8.50)
|
| Day 7, 12.0 hours post dose |
65.3
(10.95)
|
69.8
(12.39)
|
70.7
(8.36)
|
75.7
(11.47)
|
| Title | Supine Pulse Rate |
|---|---|
| Description | Pulse rate measurements were taken. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 16 | 16 | 16 | 16 |
| Day 1, 0.0 hour |
56.8
(8.89)
|
61.7
(14.30)
|
65.7
(9.26)
|
65.5
(8.44)
|
| Day 1, 0.5 hour post dose |
61.3
(9.34)
|
60.7
(10.45)
|
64.1
(8.59)
|
63.4
(9.29)
|
| Day 1, 1.0 hour post dose |
62.4
(8.97)
|
62.7
(10.19)
|
64.2
(7.49)
|
64.0
(10.39)
|
| Day 1, 2.0 hours post dose |
61.0
(9.02)
|
64.3
(12.39)
|
65.6
(8.28)
|
63.2
(8.89)
|
| Day 1, 4.0 hours post dose |
60.0
(8.51)
|
62.9
(13.29)
|
64.0
(6.51)
|
65.3
(9.65)
|
| Day 1, 8.0 hours post dose |
67.6
(11.70)
|
69.1
(11.34)
|
73.9
(10.20)
|
67.5
(10.09)
|
| Day 1, 12.0 hours post dose |
61.1
(13.36)
|
62.8
(10.83)
|
73.7
(13.52)
|
65.4
(9.68)
|
| Day 2 |
60.1
(12.18)
|
64.5
(11.95)
|
71.3
(10.58)
|
66.5
(9.20)
|
| Day 7, 0.0 hour post dose |
63.0
(11.97)
|
60.6
(12.69)
|
62.9
(5.54)
|
62.8
(8.16)
|
| Day 7, 0.5 hour post dose |
65.0
(12.63)
|
60.1
(12.07)
|
63.0
(4.36)
|
61.8
(9.35)
|
| Day 7, 1.0 hour post dose |
63.3
(13.21)
|
61.6
(11.70)
|
62.3
(5.87)
|
61.6
(7.70)
|
| Day 7, 2.0 hours post dose |
63.9
(10.42)
|
58.7
(11.49)
|
61.2
(6.17)
|
63.6
(9.16)
|
| Day 7, 4.0 hours post dose |
65.7
(10.85)
|
60.7
(11.34)
|
62.9
(6.45)
|
62.7
(9.20)
|
| Day 7, 8.0 hours post dose |
67.1
(10.20)
|
66.5
(11.80)
|
66.3
(7.34)
|
64.8
(10.83)
|
| Day 7, 12.0 hours post dose |
66.7
(13.28)
|
71.9
(17.30)
|
66.2
(6.97)
|
67.1
(11.10)
|
Adverse Events
| Time Frame | ||||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||
| Arm/Group Title | LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort | ||||
| Arm/Group Description | 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. | 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. | 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. | 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. | ||||
All Cause Mortality |
||||||||
| LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||
Serious Adverse Events |
||||||||
| LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/16 (0%) | 0/15 (0%) | 0/15 (0%) | 0/16 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| LCZ696 - Heart Failure (HF) Cohort | Valsartan - HF Cohort | LCZ696 - Hypertension (HTN) Cohort | Valsartan - HTN Cohort | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/16 (18.8%) | 1/15 (6.7%) | 1/15 (6.7%) | 3/16 (18.8%) | ||||
| Gastrointestinal disorders | ||||||||
| Abdominal pain upper | 0/16 (0%) | 0/15 (0%) | 0/15 (0%) | 1/16 (6.3%) | ||||
| Toothache | 0/16 (0%) | 0/15 (0%) | 1/15 (6.7%) | 0/16 (0%) | ||||
| Infections and infestations | ||||||||
| Nasopharyngitis | 1/16 (6.3%) | 0/15 (0%) | 0/15 (0%) | 0/16 (0%) | ||||
| Investigations | ||||||||
| Blood creatinine increased | 1/16 (6.3%) | 1/15 (6.7%) | 0/15 (0%) | 0/16 (0%) | ||||
| Nervous system disorders | ||||||||
| Dizziness | 1/16 (6.3%) | 0/15 (0%) | 0/15 (0%) | 0/16 (0%) | ||||
| Headache | 0/16 (0%) | 0/15 (0%) | 0/15 (0%) | 1/16 (6.3%) | ||||
| Presyncope | 1/16 (6.3%) | 0/15 (0%) | 0/15 (0%) | 0/16 (0%) | ||||
| Renal and urinary disorders | ||||||||
| Dysuria | 0/16 (0%) | 0/15 (0%) | 0/15 (0%) | 1/16 (6.3%) | ||||
Limitations/Caveats
Regarding LSM = 1218.56 for LCZ696 HTN cohort arm at Day 1, 1.0 hr post dose, the value was heavily inflated due to one participant with a very high change from baseline.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Novartis |
| Phone | 862-778-1873 |
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01353508
Other Study ID Numbers:
- CLCZ696B2223
First Posted:
May 13, 2011
Last Update Posted:
Nov 23, 2015
Last Verified:
Oct 1, 2015