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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01125514
• Collaborator: (none)
• Enrollment: 37
• Locations: 2
• Arms: 3
• Duration (Months): 15
• Patients Per Site: 18.5
• Patients Per Site Per Month: 1.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Aliskiren 150 mg; Drug: Furosemide 60 mg; Drug: Placebo for Aliskiren; Drug: Aliskiren 300 mg	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• 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 Start Date: May 1, 2010
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Furosemide 60 mg 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; Furosemide 60 mg commercially-available tablets; Drug: Placebo for Aliskiren; Matching placebo for aliskiren 150 mg and 300 mg
Experimental: Furosemide 60 mg + Aliskiren 150 mg 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; Aliskiren 150 mg tablet; Drug: Furosemide 60 mg; Furosemide 60 mg commercially-available tablets; Drug: Placebo for Aliskiren; Matching placebo for aliskiren 150 mg and 300 mg
Experimental: Furosemide 60 mg + Aliskiren 300 mg 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; Furosemide 60 mg commercially-available tablets; Drug: Placebo for Aliskiren; Matching placebo for aliskiren 150 mg and 300 mg; Drug: Aliskiren 300 mg; Aliskiren 300 mg tablet

Outcome Measures

Primary Outcome Measures

1. Diuretic Efficacy Index 1 for Sodium Excretion [0 to 4 hours]

   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.

2. Diuretic Efficacy Index 1 for Sodium Excretion [0 to 24 hours]

   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.

3. Diuretic Efficacy Index 2 for Water Excretion [0 to 4 hours]

   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.

4. Diuretic Efficacy Index 2 for Water Excretion [0 to 24 hours]

   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

1. Plasma Pharmacokinetics (PK) of Furosemide: Area Under the Plasma Concentration-time Curve (AUC) [pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose]

   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

2. Plasma Pharmacokinetics (PK) of Furosemide: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax, ss) [pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose]

   Cmax,ss was directly determined from the raw plasma concentration-time data.

3. Plasma Pharmacokinetics (PK) of Furosemide: Time to Reach the Maximum Concentration After Drug Administration (Tmax) [pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose]

   Tmax was directly determined from the raw plasma concentration-time data.

4. Plasma Pharmacokinetics (PK) of Furosemide: Average Steady State Plasma Concentration During Multiple Dosing (Cav,ss) [pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose]

   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

5. Plasma Pharmacokinetics (PK) of Furosemide: Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin, ss) [pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24 hours post dose]

   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]

6. Urine Pharmacokinetics (PK) of Furosemide: Amount of Drug Excreted Into the Urine From Time Zero to 24 Hours After Administration (Ae0-24) [0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose]

   The area under the plasma (or serum or blood) concentration-time curve from time zero to 24 h [mass × time × volume-1]

7. Urine Pharmacokinetics (PK) of Furosemide: Renal Clearance (CLR) [0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose]

   The renal clearance of drug [volume x time-1]

8. Creatinine Clearance [0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose]

   Creatinine clearance= (Urine creatinine/Serum creatinine) x (Urine volume/(24*60)).

9. Urine Sodium and Potassium Excretion Per Treatment at 4 Hours Postdose [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.

10. Urine Sodium and Potassium Excretion Per Treatment at 8 Hours Postdose [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.

11. Urine Sodium and Potassium Excretion Per Treatment at 12 Hours Postdose [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. Urine Sodium and Potassium Excretion Per Treatment at 24 Hours Postdose [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.

13. Mean Sitting Systolic Blood Pressure (msSBP)and Mean Sitting Diastolic Blood Pressure (msDBP) [0.5 hour pre-dose, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose.]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Berlin		Germany
2	Novartis Investigative Site	Vilnius		Lithuania

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: NCT01125514
• Other Study ID Numbers: CSPP100A2255
• First Posted: May 18, 2010
• Last Update Posted: Sep 10, 2012
• Last Verified: Aug 1, 2012

• Keywords provided by Novartis Pharmaceuticals: Heart failure,; aliskiren,; furosemide,; diuretic efficacy,; interaction
• Additional relevant MeSH terms: Heart Failure; Furosemide

Study Results

Participant Flow

Arm/Group Title	Furosemide (Fu) /Fu+Aliskiren(Alis)150mg/fu+Alis 300mg
Arm/Group 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. Day 28, no study treatment.
Period Title: Treatment Period 1 (Day 1 - Day 7)
STARTED	37
COMPLETED	35
NOT COMPLETED	2
Period Title: Treatment Period 1 (Day 1 - Day 7)
STARTED	35
Pharmacokinetic (PK) Analysis Set	33
Pharmacodynamics (PD) Analysis Set	33
COMPLETED	32
NOT COMPLETED	3
Period Title: Treatment Period 1 (Day 1 - Day 7)
STARTED	32
COMPLETED	28
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Furosemide (Fu) /Fu+Aliskiren(Alis)150mg/fu+Alis 300mg
Arm/Group 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. Day 28, no study treatment.
Overall Participants	37
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.6 (11.90)
Sex: Female, Male (Count of Participants)
Female	3 8.1%
Male	34 91.9%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg+ Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	33	32	31	28
Mean (Standard Deviation) [mmol/mg]	10.185 (4.4568)	12.122 (6.2867)	13.453 (8.3524)	12.858 (6.1040)

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg+ Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	31	31	30	28
Mean (Standard Deviation) [mmol/mg]	10.775 (5.2486)	13.264 (6.3535)	13.364 (6.1511)	14.747 (6.3531)

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	33	31	31	28
AUCtau	5217 (1996.7)	4255 (1390.6)	4638 (1532.9)	4218 (1469.3)
AUC	5217 (1996.7)	4255 (1390.6)	4638 (1532.9)	4218 (1469.3)
AUClast	5154 (1999.2)	4207 (1387.5)	4535 (1531.6)	4130 (1525.4)
AUCinf	5420 (2005.2)	4559 (1387.4)	4783 (1611.7)	4381 (1578.3)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	33	31	31	28
Mean (Standard Deviation) [ng/mL]	1702 (708.66)	1326 (518.15)	1317 (542.73)	1180 (404.92)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	33	31	31	28
Median (Full Range) [Hours]	1.500	1.500	1.500	2.00

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All subjects with evaluable pharmacokinetic parameter data with no exclusion flags and no major protocol deviations.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	33	31	31	28
Mean (Standard Deviation) [ng/mL]	217.4 (83.196)	177.3 (57.942)	193.2 (63.872)	175.8 (61.219)

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg+ Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	33	31	31	28
Mean (Standard Deviation) [ng/mL]	20.42 (25.558)	20.03 (23.780)	19.80 (29.258)	16.70 (20.868)

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg+ Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	31	31	30	28
Mean (Standard Deviation) [mg]	18.61 (5.9012)	15.08 (3.9613)	14.98 (4.5264)	13.63 (4.5134)

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	31	31	30	28
Mean (Standard Deviation) [L/h]	3.808 (1.3567)	3.841 (1.4321)	3.519 (1.3592)	3.561 (1.4458)

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	32	32	29	28
Mean (Standard Deviation) [mL/min]	104.745 (38.2884)	109.657 (30.0667)	103.841 (28.2845)	105.304 (25.4076)

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	33	32	31	28
Sodium excretion	113.992 (47.5976)	104.031 (49.5036)	98.691 (55.0495)	93.341 (43.9419)
Potassium excretion	24.555 (11.9749)	19.403 (10.5975)	23.046 (8.6829)	21.037 (7.9355)

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	33	31	31	28
Sodium excretion	129.990 (49.2835)	123.835 (56.2734)	125.677 (58.6125)	119.776 (59.0523)
Potassium excretion	33.474 (12.2417)	28.068 (12.5292)	36.120 (14.4509)	32.498 (9.6174)

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	32	32	31	27
Sodium excretion	151.254 (57.6190)	142.476 (59.1617)	144.839 (63.6708)	140.887 (68.4341)
Potassium excretion	45.013 (17.3416)	37.827 (16.0087)	46.770 (17.4395)	44.137 (11.0631)

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	31	31	30	28
Sodium excretion	185.426 (69.9537)	187.256 (69.1028)	188.886 (73.8708)	192.176 (76.0983)
Potassium excretion	57.323 (20.0607)	53.107 (21.3416)	62.715 (20.4014)	61.012 (13.6072)

15. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Safety analysis set include subjects that received study drug.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide go mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	37	35	32
0.5 predose (msSBP)	118.26 (1.62)	117.09 (1.70)	116.63 (1.80)
0.5 hour predose (msDBP)	71.70 (0.98)	71.41 (1.04)	71.39 (1.10)
0.5 hour Postdose (msSBP)	114.78 (1.64)	113.19 (1.70)	114.31 (1.80)
0.5 hour Postdose (msDBP)	70.94 (1.00)	69.04 (1.04)	69.86 (1.10)
1 hour Postdose (msSBP)	115.15 (1.64)	112.22 (1.70)	112.16 (1.80)
1 hour Postdose (msDBP)	71.22 (1.00)	69.04 (1.04)	68.96 (1.10)
2 hour Postdose (msSBP)	113.61 (1.64)	109.22 (1.70)	109.63 (1.80)
2 hour Postdose (msDBP)	68.39 (1.10)	67.50 (1.04)	68.39 (1.10)
4 hour Postdose (msSBP)	106.50 (1.64)	101.84 (1.70)	101.06 (1.80)
4 hour Postdose (msDBP)	63.85 (1.00)	62.32 (1.04)	59.07 (1.10)
8 hour Postdose (msSBP)	110.75 (1.66)	112.09 (1.70)	109.95 (1.80)
8 hour Postdose (msDBP)	66.33 (1.01)	66.94 (1.04)	66.46 (1.10)
12 hour Postdose (msSBP)	116.99 (1.66)	116.90 (1.70)	115.16 (1.80)
12 hour Postdose (msdBP)	67.86 (1.01)	68.79 (1.04)	68.50 (1.10)
24 hour Postdose (msSBP)	115.49 (1.66)	116.69 (1.72)	118.41 (1.80)
24 hour Postdose (msDBP)	71.24 (1.01)	71.66 (1.05)	72.32 (1.10)

16. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	33	32	31	28
Mean (Standard Deviation) [mL/mg]	90.402 (34.7866)	109.773 (50.2433)	119.239 (63.3655)	122.157 (58.8815)

17. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Furosemide 60 mg + Aliskiren Placebo	Furosemide 60 mg + Single Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 150mg	Furosemide 60 mg + Multiple Dose Aliskiren 300mg
Arm/Group Description	Patient received 60 mg furosemide at steady state + placebo to aliskiren from day 1 to day 7.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg on day 8.	Patient received 60 mg furosemide at steady state + single dose aliskiren 150mg ( day 9 - day 17).	Patient received 60 mg furosemide at steady state + single dose aliskiren 300mg ( day 18 - day 27).
Measure Participants	31	32	30	28
Mean (Standard Deviation) [mL/mg]	119.439 (46.2607)	151.859 (53.6734)	154.116 (40.5598)	175.112 (59.4236)

Adverse Events

Arm/Group Title	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
Arm/Group Description	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
All Cause Mortality
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious 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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/37 (5.4%)		0/33 (0%)		0/31 (0%)
Injury, poisoning and procedural complications
Rib fracture	1/37 (2.7%)		0/33 (0%)		0/31 (0%)
Metabolism and nutrition disorders
Gout	1/37 (2.7%)		0/33 (0%)		0/31 (0%)
Respiratory, thoracic and mediastinal disorders
Haemothorax	1/37 (2.7%)		0/33 (0%)		0/31 (0%)
Pneumothorax	1/37 (2.7%)		0/33 (0%)		0/31 (0%)
Other (Not Including Serious) 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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/33 (0%)		0/31 (0%)

Limitations/Caveats

[Not Specified]

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.