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

Study Overview
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Brief Summary
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Assess mechanism of action of LCZ696 related to sodium excretion.

Official Title
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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

Conditions
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Hypertension

Intervention / Treatment
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* Drug: LCZ696
* Drug: Valsartan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCZ696 to Valsartan - Heart Failure (HF) cohort<br>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<br>* 200 mg and 400 mg tablets<br>Drug: Valsartan<br>* 160 mg tablets<br>|
| Experimental: Valsartan to LCZ696 - HF Cohort<br>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<br>* 200 mg and 400 mg tablets<br>Drug: Valsartan<br>* 160 mg tablets<br>|
| Experimental: LCZ696 to Valsartan - Hypertension (HTN) cohort<br>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<br>* 200 mg and 400 mg tablets<br>Drug: Valsartan<br>* 160 mg tablets<br>|
| Experimental: Valsartan to LCZ696 - HTN cohort<br>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<br>* 200 mg and 400 mg tablets<br>Drug: Valsartan<br>* 160 mg tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-hour Urinary Sodium Excretion | 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). | day 1 | 
| Cumulative 7-day Urinary Sodium Excretion | 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). | 7 day-cummulative (days 1 through 7) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-hour Diuresis | 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. | day 1 | 
| 7-day Cumulative Diuresis | 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 (days 1 through 7) | 
| Urinary Cyclic Guanosine Monophosphate (cGMP) Excretion Over 24 Hours | cGMP was analyzed at a central laboratory. The measure type used for this OM was Geometric LSM. | day 1, day 6, day 7 | 
| Percent Change From Baseline in Plasma Mid-regional Pro-atrial Natriuretic Peptide (MR-proANP) Biomarker | MR-proANP was analyzed at a central laboratory. | 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 | 
| Percent Change From Baseline in Brain Natriuretic Peptide (BNP) Biomarker | BNP was analyzed at a central laboratory. | 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 | 
| Percent Change From Baseline in Mid-regional Pro-adrenomedullin (MR-proADM) Biomarker | MR-proADM was analyzed at a central laboratory. | 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 | 
| Percent Change From Baseline in C-type Natriuretic Peptide (proCNP) Biomarker | ProCNP was analyzed at a central laboratory. | 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 | 
| Percent Change From Baseline in C-terminal-proendothelin-1 (CT-proET-1) Biomarker | CT-proET-1 was analyzed at a central laboratory. | 12 hours post dose on day 1; 24 hours post dose on day 2; 0 and 12 hours post dose on day 7 | 
| Percent Change From Baseline in N-terminal-proBNP (NT-proBNP) Biomarker | NT-proBNP was analyzed at a central laboratory. | 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 | 
| Percent Change From Baseline in Aldosterone Biomarker | Aldosterone was analyzed at a central laboratory. | 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 | 
| Percent Change From Baseline in Urinary Electrolyte Excretion (Sodium, Potassium, Chloride and Calcium) | Urine was collected in 12-hour intervals, and of each pooled 24-hour (daily) sample, sodium, potassium, albumin and calcium were measured. | 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 | 
| Percent Change From Baseline in Blood Plasma Creatinine | Blood plasma creatinine was analyzed at a central laboratory. | 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 | 
| Glomerular Filtration Rate (GFR) Over Time | GFR was used as a measure of renal function. | 0, 2, 4 and 6 hours post dose on day 1; 0, 2, 4 and 6 hours post dose on day 7 | 
| Renal Blood Flow (RBF) Over Time | RBF was used as a measure of renal function. | 0, 2, 4 and 6 hours post dose on day 1; 0, 2, 4 and 6 hours post dose on day 7 | 
| Supine Systolic Blood Pressure | Systolic blood pressure measurements were taken. | 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 | 
| Supine Diastolic Blood Pressure | Diastolic blood pressure measurements were taken. | 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 | 
| Supine Pulse Rate | Pulse rate measurements were taken. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sodium excretion,, LCZ696