A Study to Investigate the Pharmacodynamic and Pharmacokinetic Interaction Between Aliskiren and Furosemide in Patients With Heart Failure

Study Overview
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Brief Summary
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This study assessed the interaction between single and multiple doses of aliskiren (150 mg and 300 mg) and furosemide (60 mg) in patients with heart failure.

Official Title
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A Single-blind, Multiple Dose, Placebo-controlled, Double Dummy Study to Investigate the Pharmacodynamic and Pharmacokinetic Interaction Between Aliskiren and Furosemide in Patients With Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Aliskiren 150 mg
* Drug: Furosemide 60 mg
* Drug: Placebo for Aliskiren
* Drug: Aliskiren 300 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Systolic or diastolic heart failure, diagnosed with either NYHA functional class II to III at least 3 months prior to screening and on stable medication for at least 12 weeks. Patients must have met either of the criteria at screening: Documented left ventricular ejection fraction (LVEF) greater than 20% but lower than 40% OR Patients with a documented LVEF greater than 40% and with a history of NT-pro-BNP> 400pg/mL (or BNP > 100pg/mL) within 12 months of screening. Exclusion Criteria: Treatment with Angiotensin Receptor Blockers (ARBs), aldosterone receptor antagonists and diuretics (other than furosemide) within 3 weeks of first dose and during the study. Beta blockers were permitted provided the dose was stable for at least 3 weeks before the first dose and remains so throughout the study. Hypertrophic cardiomyopathy (HCMP). If a subject is currently treated with furosemide, the dose must be stable for at least 3 weeks before the first dose and the dose must not exceed 60 mg daily Stable heart failure requiring treatment with both an ACE inhibitor and an ARB or Current acute decompensated heart failure. Mean sitting systolic blood pressure ≥160 mmHg and/or mean sitting diastolic blood pressure ≥ 100mmHg and/or secondary forms of hypertension. Persistent sitting systolic blood pressure <90 mmHg. History of angioedema. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Furosemide 60 mg<br>Treatment period 1 (Day 1 to Day 7): All eligible patients received 60 mg furosemide, 150 mg placebo of aliskiren, and 300 mg placebo aliskiren once daily. | Drug: Furosemide 60 mg<br>* Furosemide 60 mg commercially-available tablets<br>Drug: Placebo for Aliskiren<br>* Matching placebo for aliskiren 150 mg and 300 mg<br>|
| Experimental: Furosemide 60 mg + Aliskiren 150 mg<br>Treatment Period 2 (Day 8 to day 17): Patients received 60 mg furosemide, 150 mg aliskiren and 300 mg placebo once daily. | Drug: Aliskiren 150 mg<br>* Aliskiren 150 mg tablet<br>Drug: Furosemide 60 mg<br>* Furosemide 60 mg commercially-available tablets<br>Drug: Placebo for Aliskiren<br>* Matching placebo for aliskiren 150 mg and 300 mg<br>|
| Experimental: Furosemide 60 mg + Aliskiren 300 mg<br>Treatment Period 3 (Day 18 to day 27): Patients received 60 mg furosemide, 300 mg aliskiren and 150 mg placebo of aliskiren once daily. | Drug: Furosemide 60 mg<br>* Furosemide 60 mg commercially-available tablets<br>Drug: Placebo for Aliskiren<br>* Matching placebo for aliskiren 150 mg and 300 mg<br>Drug: Aliskiren 300 mg<br>* Aliskiren 300 mg tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diuretic Efficacy Index 1 for Sodium Excretion | Efficacy of furosemide for sodium excretion (efficacy index 1) was defined by dividing urinary sodium excretion by the urinary excretion of furosemide. Diuretic index 1 for sodium was calculated for the for the total 0 to 4 hour urine collection. | 0 to 4 hours | 
| Diuretic Efficacy Index 1 for Sodium Excretion | Efficacy of furosemide for sodium excretion (efficacy index 1) was defined by dividing urinary sodium excretion by the urinary excretion of furosemide. Diuretic index 1 for sodium was calculated for the for the total 0 to 24 hour urine collection. | 0 to 24 hours | 
| Diuretic Efficacy Index 2 for Water Excretion | Efficacy of furosemide for water excretion (efficacy index 2) was defined by dividing urine volume by the urinary excretion of furosemide.Diuretic index 2 for water was calculated for the 0 to 4 hour fraction urine collection. | 0 to 4 hours | 
| Diuretic Efficacy Index 2 for Water Excretion | Efficacy of furosemide for water excretion (efficacy index 2) was defined by dividing urine volume by the urinary excretion of furosemide.Diuretic index 2 for water was calculated for the 0 to 4 hour fraction and for the total 0 to 24 hour urine collection. | 0 to 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Pharmacokinetics (PK) of Furosemide: Area Under the Plasma Concentration-time Curve (AUC) | Pharmacokinetic (PK) parameters were determined from the plasma concentration time profile of furosemide using a non-compartmental method: AUCtau: Area under the plasma concentration-time curve from time zero to the end of the dosing interval AUC (0-24): Area under the plasma concentration-time curve from time zero to 24 hours AUClast: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated as the sum of linear trapezoids using non-compartmental analysis. AUCinf: Area under the plasma concentration-time curve from time zero to infinity. AUCinf was calculated by adding AUClast and the value obtained from dividing the last measurable plasma concentration by λz, where λz was determined from automated linear regression of the last three time points with non-zero concentrations in the terminal phase of the log-transformed concentration-time profile | pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose | 
| Plasma Pharmacokinetics (PK) of Furosemide: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax, ss) | Cmax,ss was directly determined from the raw plasma concentration-time data. | pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose | 
| Plasma Pharmacokinetics (PK) of Furosemide: Time to Reach the Maximum Concentration After Drug Administration (Tmax) | Tmax was directly determined from the raw plasma concentration-time data. | pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose | 
| Plasma Pharmacokinetics (PK) of Furosemide: Average Steady State Plasma Concentration During Multiple Dosing (Cav,ss) | The average steady-state drug concentration in the plasma, blood, serum, or other body fluids during multiple dosing [amount x volume-1]. This was estimated as AUCτ/τ | pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose | 
| Plasma Pharmacokinetics (PK) of Furosemide: Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin, ss) | The minimum observed steady-state drug concentration in the plasma, blood, serum, or other body fluids at the end of the dosing interval during multiple dosing [amount x volume-1] | pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24 hours post dose | 
| Urine Pharmacokinetics (PK) of Furosemide: Amount of Drug Excreted Into the Urine From Time Zero to 24 Hours After Administration (Ae0-24) | The area under the plasma (or serum or blood) concentration-time curve from time zero to 24 h [mass × time × volume-1] | 0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose | 
| Urine Pharmacokinetics (PK) of Furosemide: Renal Clearance (CLR) | The renal clearance of drug [volume x time-1] | 0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose | 
| Creatinine Clearance | Creatinine clearance= (Urine creatinine/Serum creatinine) x (Urine volume/(24*60)). | 0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose | 
| Urine Sodium and Potassium Excretion Per Treatment at 4 Hours Postdose | Urine was collected 4 hours postdose in all treatment groups for sodium and potassium analysis. Each patient was required to void their bladder before drug administration and at the end 4 hours. | 4 hours postdose | 
| Urine Sodium and Potassium Excretion Per Treatment at 8 Hours Postdose | Urine was collected 8 hours postdose in all treatment groups for sodium and potassium analysis. Each patient was required to void their bladder before drug administration and at the end 8 hours. | 8 hours postdose | 
| Urine Sodium and Potassium Excretion Per Treatment at 12 Hours Postdose | Urine was collected 12 hours postdose in all treatment groups for sodium and potassium analysis. Each patient was required to void their bladder before drug administration and at the end 12 hours. | 12 hours postdose | 
| Urine Sodium and Potassium Excretion Per Treatment at 24 Hours Postdose | Urine was collected 24 hours postdose in all treatment groups for sodium and potassium analysis. Each patient was required to void their bladder before drug administration and at the end 24 hours. | 24 hours postdose | 
| Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP) | Sitting blood pressure was measured three times at 1 to 2-minute intervals. The mean of the three sitting blood pressure measurements was used as the average of the sitting office blood pressure. The msSBP and msDBP data were analyzed using a mixed effect model with fixed effects from treatment and treatment*time; random effect from patients and predose as covariate. | 0.5 hour pre-dose, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure,, aliskiren,, furosemide,, diuretic efficacy,, interaction