Back to resultsA Study to Investigate the Pharmacodynamic and Pharmacokinetic Interaction Between Aliskiren and Furosemide in Patients With Heart Failure
Primary Purpose
Heart Failure
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Aliskiren 150 mg
Furosemide 60 mg
Placebo for Aliskiren
Aliskiren 300 mg
Sponsored by
About this trial
This is an interventional treatment trial for Heart Failure focused on measuring Heart failure,, aliskiren,, furosemide,, diuretic efficacy,, interaction
Eligibility Criteria
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
Sites / Locations
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Furosemide 60 mg
Furosemide 60 mg + Aliskiren 150 mg
Furosemide 60 mg + Aliskiren 300 mg
Arm Description
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.
Treatment Period 2 (Day 8 to day 17): Patients received 60 mg furosemide, 150 mg aliskiren and 300 mg placebo once daily.
Treatment Period 3 (Day 18 to day 27): Patients received 60 mg furosemide, 300 mg aliskiren and 150 mg placebo of aliskiren once daily.
Outcomes
Primary Outcome Measures
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.
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.
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.
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.
Secondary Outcome Measures
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
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.
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.
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
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]
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]
Urine Pharmacokinetics (PK) of Furosemide: Renal Clearance (CLR)
The renal clearance of drug [volume x time-1]
Creatinine Clearance
Creatinine clearance= (Urine creatinine/Serum creatinine) x (Urine volume/(24*60)).
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01125514
Brief Title
A Study to Investigate the Pharmacodynamic and Pharmacokinetic Interaction Between Aliskiren and Furosemide in Patients With Heart Failure
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
August 2012
Overall Recruitment Status
Completed
Study Start Date
May 2010 (undefined)
Primary Completion Date
August 2011 (Actual)
Study Completion Date
August 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure
Keywords
Heart failure,, aliskiren,, furosemide,, diuretic efficacy,, interaction
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
Participant
Allocation
Non-Randomized
Enrollment
37 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Furosemide 60 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Furosemide 60 mg + Aliskiren 150 mg
Arm Type
Experimental
Arm Description
Treatment Period 2 (Day 8 to day 17): Patients received 60 mg furosemide, 150 mg aliskiren and 300 mg placebo once daily.
Arm Title
Furosemide 60 mg + Aliskiren 300 mg
Arm Type
Experimental
Arm Description
Treatment Period 3 (Day 18 to day 27): Patients received 60 mg furosemide, 300 mg aliskiren and 150 mg placebo of aliskiren once daily.
Intervention Type
Drug
Intervention Name(s)
Aliskiren 150 mg
Intervention Description
Aliskiren 150 mg tablet
Intervention Type
Drug
Intervention Name(s)
Furosemide 60 mg
Intervention Description
Furosemide 60 mg commercially-available tablets
Intervention Type
Drug
Intervention Name(s)
Placebo for Aliskiren
Intervention Description
Matching placebo for aliskiren 150 mg and 300 mg
Intervention Type
Drug
Intervention Name(s)
Aliskiren 300 mg
Intervention Description
Aliskiren 300 mg tablet
Primary Outcome Measure Information:
Title
Diuretic Efficacy Index 1 for Sodium Excretion
Description
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.
Time Frame
0 to 4 hours
Title
Diuretic Efficacy Index 1 for Sodium Excretion
Description
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.
Time Frame
0 to 24 hours
Title
Diuretic Efficacy Index 2 for Water Excretion
Description
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.
Time Frame
0 to 4 hours
Title
Diuretic Efficacy Index 2 for Water Excretion
Description
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.
Time Frame
0 to 24 hours
Secondary Outcome Measure Information:
Title
Plasma Pharmacokinetics (PK) of Furosemide: Area Under the Plasma Concentration-time Curve (AUC)
Description
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
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose
Title
Plasma Pharmacokinetics (PK) of Furosemide: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax, ss)
Description
Cmax,ss was directly determined from the raw plasma concentration-time data.
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose
Title
Plasma Pharmacokinetics (PK) of Furosemide: Time to Reach the Maximum Concentration After Drug Administration (Tmax)
Description
Tmax was directly determined from the raw plasma concentration-time data.
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose
Title
Plasma Pharmacokinetics (PK) of Furosemide: Average Steady State Plasma Concentration During Multiple Dosing (Cav,ss)
Description
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
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose
Title
Plasma Pharmacokinetics (PK) of Furosemide: Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin, ss)
Description
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]
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24 hours post dose
Title
Urine Pharmacokinetics (PK) of Furosemide: Amount of Drug Excreted Into the Urine From Time Zero to 24 Hours After Administration (Ae0-24)
Description
The area under the plasma (or serum or blood) concentration-time curve from time zero to 24 h [mass × time × volume-1]
Time Frame
0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose
Title
Urine Pharmacokinetics (PK) of Furosemide: Renal Clearance (CLR)
Description
The renal clearance of drug [volume x time-1]
Time Frame
0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose
Title
Creatinine Clearance
Description
Creatinine clearance= (Urine creatinine/Serum creatinine) x (Urine volume/(24*60)).
Time Frame
0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose
Title
Urine Sodium and Potassium Excretion Per Treatment at 4 Hours Postdose
Description
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.
Time Frame
4 hours postdose
Title
Urine Sodium and Potassium Excretion Per Treatment at 8 Hours Postdose
Description
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.
Time Frame
8 hours postdose
Title
Urine Sodium and Potassium Excretion Per Treatment at 12 Hours Postdose
Description
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.
Time Frame
12 hours postdose
Title
Urine Sodium and Potassium Excretion Per Treatment at 24 Hours Postdose
Description
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.
Time Frame
24 hours postdose
Title
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
Description
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.
Time Frame
0.5 hour pre-dose, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Berlin
Country
Germany
Facility Name
Novartis Investigative Site
City
Vilnius
Country
Lithuania
12. IPD Sharing Statement
Learn more about this trial
A Study to Investigate the Pharmacodynamic and Pharmacokinetic Interaction Between Aliskiren and Furosemide in Patients With Heart Failure
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