Trial Outcomes & Findings for A Study to Investigate the Pharmacodynamic and Pharmacokinetic Interaction Between Aliskiren and Furosemide in Patients With Heart Failure (NCT NCT01125514)
NCT ID: NCT01125514
Last Updated: 2012-09-10
Results Overview
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.
COMPLETED
PHASE2
37 participants
0 to 4 hours
2012-09-10
Participant Flow
Participant milestones
| Measure |
Furosemide (Fu) /Fu+Aliskiren(Alis)150mg/fu+Alis 300mg
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.
Day 28, no study treatment.
|
|---|---|
|
Treatment Period 1 (Day 1 - Day 7)
STARTED
|
37
|
|
Treatment Period 1 (Day 1 - Day 7)
COMPLETED
|
35
|
|
Treatment Period 1 (Day 1 - Day 7)
NOT COMPLETED
|
2
|
|
Treatment Period 2 (Day 8 - Day 17)
STARTED
|
35
|
|
Treatment Period 2 (Day 8 - Day 17)
Pharmacokinetic (PK) Analysis Set
|
33
|
|
Treatment Period 2 (Day 8 - Day 17)
Pharmacodynamics (PD) Analysis Set
|
33
|
|
Treatment Period 2 (Day 8 - Day 17)
COMPLETED
|
32
|
|
Treatment Period 2 (Day 8 - Day 17)
NOT COMPLETED
|
3
|
|
Treatment Period2(Day9-Day27) and Day 28
STARTED
|
32
|
|
Treatment Period2(Day9-Day27) and Day 28
COMPLETED
|
28
|
|
Treatment Period2(Day9-Day27) and Day 28
NOT COMPLETED
|
4
|
Reasons for withdrawal
| Measure |
Furosemide (Fu) /Fu+Aliskiren(Alis)150mg/fu+Alis 300mg
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.
Day 28, no study treatment.
|
|---|---|
|
Treatment Period 1 (Day 1 - Day 7)
Adverse Event
|
1
|
|
Treatment Period 1 (Day 1 - Day 7)
Administrative problems
|
1
|
|
Treatment Period 2 (Day 8 - Day 17)
Adverse Event
|
3
|
|
Treatment Period2(Day9-Day27) and Day 28
Adverse Event
|
2
|
|
Treatment Period2(Day9-Day27) and Day 28
Protocol Deviation
|
1
|
|
Treatment Period2(Day9-Day27) and Day 28
Withdrawal by Subject
|
1
|
Baseline Characteristics
A Study to Investigate the Pharmacodynamic and Pharmacokinetic Interaction Between Aliskiren and Furosemide in Patients With Heart Failure
Baseline characteristics by cohort
| Measure |
Furosemide (Fu) /Fu+Aliskiren(Alis)150mg/fu+Alis 300mg
n=37 Participants
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.
Day 28, no study treatment.
|
|---|---|
|
Age Continuous
|
59.6 years
STANDARD_DEVIATION 11.90 • n=5 Participants
|
|
Sex: Female, Male
Female
|
3 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
34 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 0 to 4 hoursPopulation: All patients who received at least one dose of study drug and had evaluable pharmacodynamic (PD) data with no major protocol deviation in at least one period were included in the PD analysis set.
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.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=33 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=32 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Diuretic Efficacy Index 1 for Sodium Excretion
|
10.185 mmol/mg
Standard Deviation 4.4568
|
12.122 mmol/mg
Standard Deviation 6.2867
|
13.453 mmol/mg
Standard Deviation 8.3524
|
12.858 mmol/mg
Standard Deviation 6.1040
|
PRIMARY outcome
Timeframe: 0 to 24 hoursPopulation: All patients who received at least one dose of study drug and had evaluable pharmacodynamic (PD) data with no major protocol deviation in at least one period were included in the PD analysis set.
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.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=31 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=30 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Diuretic Efficacy Index 1 for Sodium Excretion
|
10.775 mmol/mg
Standard Deviation 5.2486
|
13.264 mmol/mg
Standard Deviation 6.3535
|
13.364 mmol/mg
Standard Deviation 6.1511
|
14.747 mmol/mg
Standard Deviation 6.3531
|
PRIMARY outcome
Timeframe: 0 to 4 hoursPopulation: All patients who received at least one dose of study drug and had evaluable PD data with no major protocol deviation in at least one period were included in the PD analysis set.
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.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=33 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=32 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Diuretic Efficacy Index 2 for Water Excretion
|
90.402 mL/mg
Standard Deviation 34.7866
|
109.773 mL/mg
Standard Deviation 50.2433
|
119.239 mL/mg
Standard Deviation 63.3655
|
122.157 mL/mg
Standard Deviation 58.8815
|
PRIMARY outcome
Timeframe: 0 to 24 hoursPopulation: All patients who received at least one dose of study drug and had evaluable PD data with no major protocol deviation in at least one period were included in the PD analysis set.
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.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=31 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=32 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=30 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Diuretic Efficacy Index 2 for Water Excretion
|
119.439 mL/mg
Standard Deviation 46.2607
|
151.859 mL/mg
Standard Deviation 53.6734
|
154.116 mL/mg
Standard Deviation 40.5598
|
175.112 mL/mg
Standard Deviation 59.4236
|
SECONDARY outcome
Timeframe: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dosePopulation: All patients who received at least one dose of study drug and had evaluable Pharmacokinetic (PK) data with no major protocol deviation in at least one period were included in the PK analysis set.
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
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=33 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Plasma Pharmacokinetics (PK) of Furosemide: Area Under the Plasma Concentration-time Curve (AUC)
AUClast
|
5154 h*ng/mL
Standard Deviation 1999.2
|
4207 h*ng/mL
Standard Deviation 1387.5
|
4535 h*ng/mL
Standard Deviation 1531.6
|
4130 h*ng/mL
Standard Deviation 1525.4
|
|
Plasma Pharmacokinetics (PK) of Furosemide: Area Under the Plasma Concentration-time Curve (AUC)
AUCtau
|
5217 h*ng/mL
Standard Deviation 1996.7
|
4255 h*ng/mL
Standard Deviation 1390.6
|
4638 h*ng/mL
Standard Deviation 1532.9
|
4218 h*ng/mL
Standard Deviation 1469.3
|
|
Plasma Pharmacokinetics (PK) of Furosemide: Area Under the Plasma Concentration-time Curve (AUC)
AUC
|
5217 h*ng/mL
Standard Deviation 1996.7
|
4255 h*ng/mL
Standard Deviation 1390.6
|
4638 h*ng/mL
Standard Deviation 1532.9
|
4218 h*ng/mL
Standard Deviation 1469.3
|
|
Plasma Pharmacokinetics (PK) of Furosemide: Area Under the Plasma Concentration-time Curve (AUC)
AUCinf
|
5420 h*ng/mL
Standard Deviation 2005.2
|
4559 h*ng/mL
Standard Deviation 1387.4
|
4783 h*ng/mL
Standard Deviation 1611.7
|
4381 h*ng/mL
Standard Deviation 1578.3
|
SECONDARY outcome
Timeframe: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dosePopulation: All patients who received at least one dose of study drug and had evaluable pharmacokinetic (PK) data with no major protocol deviation in at least one period were included in the PK analysis set
Cmax,ss was directly determined from the raw plasma concentration-time data.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=33 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Plasma Pharmacokinetics (PK) of Furosemide: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax, ss)
|
1702 ng/mL
Standard Deviation 708.66
|
1326 ng/mL
Standard Deviation 518.15
|
1317 ng/mL
Standard Deviation 542.73
|
1180 ng/mL
Standard Deviation 404.92
|
SECONDARY outcome
Timeframe: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dosePopulation: All patients who received at least one dose of study drug and had evaluable PK data with no major protocol deviation in at least one period were included in the PK analysis set
Tmax was directly determined from the raw plasma concentration-time data.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=33 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Plasma Pharmacokinetics (PK) of Furosemide: Time to Reach the Maximum Concentration After Drug Administration (Tmax)
|
1.500 Hours
Interval 1.0 to 3.0
|
1.500 Hours
Interval 0.5 to 3.0
|
1.500 Hours
Interval 1.0 to 4.0
|
2.00 Hours
Interval 0.5 to 3.0
|
SECONDARY outcome
Timeframe: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dosePopulation: All subjects with evaluable pharmacokinetic parameter data with no exclusion flags and no major protocol deviations.
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
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=33 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Plasma Pharmacokinetics (PK) of Furosemide: Average Steady State Plasma Concentration During Multiple Dosing (Cav,ss)
|
217.4 ng/mL
Standard Deviation 83.196
|
177.3 ng/mL
Standard Deviation 57.942
|
193.2 ng/mL
Standard Deviation 63.872
|
175.8 ng/mL
Standard Deviation 61.219
|
SECONDARY outcome
Timeframe: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24 hours post dosePopulation: All patients who received at least one dose of study drug and had evaluable PK data with no major protocol deviation in at least one period were included in the PK analysis set
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 \[amount x volume-1\]
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=33 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Plasma Pharmacokinetics (PK) of Furosemide: Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin, ss)
|
20.42 ng/mL
Standard Deviation 25.558
|
20.03 ng/mL
Standard Deviation 23.780
|
19.80 ng/mL
Standard Deviation 29.258
|
16.70 ng/mL
Standard Deviation 20.868
|
SECONDARY outcome
Timeframe: 0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dosePopulation: All patients who received at least one dose of study drug and had evaluable PK data with no major protocol deviation in at least one period were included in the PK analysis set
The area under the plasma (or serum or blood) concentration-time curve from time zero to 24 h \[mass × time × volume-1\]
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=31 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=30 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Urine Pharmacokinetics (PK) of Furosemide: Amount of Drug Excreted Into the Urine From Time Zero to 24 Hours After Administration (Ae0-24)
|
18.61 mg
Standard Deviation 5.9012
|
15.08 mg
Standard Deviation 3.9613
|
14.98 mg
Standard Deviation 4.5264
|
13.63 mg
Standard Deviation 4.5134
|
SECONDARY outcome
Timeframe: 0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dosePopulation: All patients who received at least one dose of study drug and had evaluable pharmacodynamic (PD) data with no major protocol deviation in at least one period were included in the PD analysis set.
The renal clearance of drug \[volume x time-1\]
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=31 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=30 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Urine Pharmacokinetics (PK) of Furosemide: Renal Clearance (CLR)
|
3.808 L/h
Standard Deviation 1.3567
|
3.841 L/h
Standard Deviation 1.4321
|
3.519 L/h
Standard Deviation 1.3592
|
3.561 L/h
Standard Deviation 1.4458
|
SECONDARY outcome
Timeframe: 0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dosePopulation: All patients who received at least one dose of study drug and had evaluable PD data with no major protocol deviation in at least one period were included in the PD analysis set.
Creatinine clearance= (Urine creatinine/Serum creatinine) x (Urine volume/(24\*60)).
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=32 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=32 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=29 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Creatinine Clearance
|
104.745 mL/min
Standard Deviation 38.2884
|
109.657 mL/min
Standard Deviation 30.0667
|
103.841 mL/min
Standard Deviation 28.2845
|
105.304 mL/min
Standard Deviation 25.4076
|
SECONDARY outcome
Timeframe: 4 hours postdosePopulation: All patients who received at least one dose of study drug and had evaluable pharmacodynamics (PD)data with no major protocol deviation in at least one period were included in the PD analysis set.
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.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=33 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=32 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Urine Sodium and Potassium Excretion Per Treatment at 4 Hours Postdose
Sodium excretion
|
113.992 mmol
Standard Deviation 47.5976
|
104.031 mmol
Standard Deviation 49.5036
|
98.691 mmol
Standard Deviation 55.0495
|
93.341 mmol
Standard Deviation 43.9419
|
|
Urine Sodium and Potassium Excretion Per Treatment at 4 Hours Postdose
Potassium excretion
|
24.555 mmol
Standard Deviation 11.9749
|
19.403 mmol
Standard Deviation 10.5975
|
23.046 mmol
Standard Deviation 8.6829
|
21.037 mmol
Standard Deviation 7.9355
|
SECONDARY outcome
Timeframe: 8 hours postdosePopulation: All patients who received at least one dose of study drug and had evaluable pharmacodynamics (PD)data with no major protocol deviation in at least one period were included in the PD analysis set.
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.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=33 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Urine Sodium and Potassium Excretion Per Treatment at 8 Hours Postdose
Sodium excretion
|
129.990 mmol
Standard Deviation 49.2835
|
123.835 mmol
Standard Deviation 56.2734
|
125.677 mmol
Standard Deviation 58.6125
|
119.776 mmol
Standard Deviation 59.0523
|
|
Urine Sodium and Potassium Excretion Per Treatment at 8 Hours Postdose
Potassium excretion
|
33.474 mmol
Standard Deviation 12.2417
|
28.068 mmol
Standard Deviation 12.5292
|
36.120 mmol
Standard Deviation 14.4509
|
32.498 mmol
Standard Deviation 9.6174
|
SECONDARY outcome
Timeframe: 12 hours postdosePopulation: All patients who received at least one dose of study drug and had evaluable pharmacodynamics (PD)data with no major protocol deviation in at least one period were included in the PD analysis set.
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.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=32 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=32 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=27 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Urine Sodium and Potassium Excretion Per Treatment at 12 Hours Postdose
Sodium excretion
|
151.254 mmol
Standard Deviation 57.6190
|
142.476 mmol
Standard Deviation 59.1617
|
144.839 mmol
Standard Deviation 63.6708
|
140.887 mmol
Standard Deviation 68.4341
|
|
Urine Sodium and Potassium Excretion Per Treatment at 12 Hours Postdose
Potassium excretion
|
45.013 mmol
Standard Deviation 17.3416
|
37.827 mmol
Standard Deviation 16.0087
|
46.770 mmol
Standard Deviation 17.4395
|
44.137 mmol
Standard Deviation 11.0631
|
SECONDARY outcome
Timeframe: 24 hours postdosePopulation: All patients who received at least one dose of study drug and had evaluable pharmacodynamics (PD)data with no major protocol deviation in at least one period were included in the PD analysis set.
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.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=31 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=31 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=30 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
n=28 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Urine Sodium and Potassium Excretion Per Treatment at 24 Hours Postdose
Sodium excretion
|
185.426 mmol
Standard Deviation 69.9537
|
187.256 mmol
Standard Deviation 69.1028
|
188.886 mmol
Standard Deviation 73.8708
|
192.176 mmol
Standard Deviation 76.0983
|
|
Urine Sodium and Potassium Excretion Per Treatment at 24 Hours Postdose
Potassium excretion
|
57.323 mmol
Standard Deviation 20.0607
|
53.107 mmol
Standard Deviation 21.3416
|
62.715 mmol
Standard Deviation 20.4014
|
61.012 mmol
Standard Deviation 13.6072
|
SECONDARY outcome
Timeframe: 0.5 hour pre-dose, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose.Population: Safety analysis set include subjects that received study drug.
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.
Outcome measures
| Measure |
Furosemide 60 mg + Aliskiren Placebo
n=37 Participants
Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.
|
Furosemide 60 mg+ Single Dose Aliskiren 150mg
n=35 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.
|
Furosemide 60 mg + Multiple Dose Aliskiren 150mg
n=32 Participants
Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).
|
Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
|
|---|---|---|---|---|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
0.5 hour Postdose (msSBP)
|
114.78 mmHg
Standard Error 1.64
|
113.19 mmHg
Standard Error 1.70
|
114.31 mmHg
Standard Error 1.80
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
4 hour Postdose (msSBP)
|
106.50 mmHg
Standard Error 1.64
|
101.84 mmHg
Standard Error 1.70
|
101.06 mmHg
Standard Error 1.80
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
0.5 predose (msSBP)
|
118.26 mmHg
Standard Error 1.62
|
117.09 mmHg
Standard Error 1.70
|
116.63 mmHg
Standard Error 1.80
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
0.5 hour predose (msDBP)
|
71.70 mmHg
Standard Error 0.98
|
71.41 mmHg
Standard Error 1.04
|
71.39 mmHg
Standard Error 1.10
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
0.5 hour Postdose (msDBP)
|
70.94 mmHg
Standard Error 1.00
|
69.04 mmHg
Standard Error 1.04
|
69.86 mmHg
Standard Error 1.10
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
1 hour Postdose (msSBP)
|
115.15 mmHg
Standard Error 1.64
|
112.22 mmHg
Standard Error 1.70
|
112.16 mmHg
Standard Error 1.80
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
1 hour Postdose (msDBP)
|
71.22 mmHg
Standard Error 1.00
|
69.04 mmHg
Standard Error 1.04
|
68.96 mmHg
Standard Error 1.10
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
2 hour Postdose (msSBP)
|
113.61 mmHg
Standard Error 1.64
|
109.22 mmHg
Standard Error 1.70
|
109.63 mmHg
Standard Error 1.80
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
2 hour Postdose (msDBP)
|
68.39 mmHg
Standard Error 1.10
|
67.50 mmHg
Standard Error 1.04
|
68.39 mmHg
Standard Error 1.10
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
4 hour Postdose (msDBP)
|
63.85 mmHg
Standard Error 1.00
|
62.32 mmHg
Standard Error 1.04
|
59.07 mmHg
Standard Error 1.10
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
8 hour Postdose (msSBP)
|
110.75 mmHg
Standard Error 1.66
|
112.09 mmHg
Standard Error 1.70
|
109.95 mmHg
Standard Error 1.80
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
8 hour Postdose (msDBP)
|
66.33 mmHg
Standard Error 1.01
|
66.94 mmHg
Standard Error 1.04
|
66.46 mmHg
Standard Error 1.10
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
12 hour Postdose (msSBP)
|
116.99 mmHg
Standard Error 1.66
|
116.90 mmHg
Standard Error 1.70
|
115.16 mmHg
Standard Error 1.80
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
12 hour Postdose (msdBP)
|
67.86 mmHg
Standard Error 1.01
|
68.79 mmHg
Standard Error 1.04
|
68.50 mmHg
Standard Error 1.10
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
24 hour Postdose (msSBP)
|
115.49 mmHg
Standard Error 1.66
|
116.69 mmHg
Standard Error 1.72
|
118.41 mmHg
Standard Error 1.80
|
—
|
|
Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP)
24 hour Postdose (msDBP)
|
71.24 mmHg
Standard Error 1.01
|
71.66 mmHg
Standard Error 1.05
|
72.32 mmHg
Standard Error 1.10
|
—
|
Adverse Events
60 mg Furosemide + 150 mg Placebo + 300 mg Placebo
60 mg Furosemide + 150 mg Aliskiren + 300 mg Placebo
60 mg Furosemide + 300 mg Aliskiren + 150 mg Placebo
Serious adverse events
| Measure |
60 mg Furosemide + 150 mg Placebo + 300 mg Placebo
n=37 participants at risk
60 mg furosemide + 150 mg placebo + 300 mg placebo
|
60 mg Furosemide + 150 mg Aliskiren + 300 mg Placebo
n=33 participants at risk
60 mg furosemide + 150 mg aliskiren + 300 mg placebo
|
60 mg Furosemide + 300 mg Aliskiren + 150 mg Placebo
n=31 participants at risk
60 mg furosemide + 300 mg aliskiren + 150 mg placebo
|
|---|---|---|---|
|
Injury, poisoning and procedural complications
Rib fracture
|
2.7%
1/37
|
0.00%
0/33
|
0.00%
0/31
|
|
Metabolism and nutrition disorders
Gout
|
2.7%
1/37
|
0.00%
0/33
|
0.00%
0/31
|
|
Respiratory, thoracic and mediastinal disorders
Haemothorax
|
2.7%
1/37
|
0.00%
0/33
|
0.00%
0/31
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax
|
2.7%
1/37
|
0.00%
0/33
|
0.00%
0/31
|
Other adverse events
Adverse event data not reported
Additional Information
Study Director
Novartis Pharmaceuticals
Results disclosure agreements
- Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
- Publication restrictions are in place
Restriction type: OTHER