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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01125514
First received: May 17, 2010
Last updated: August 9, 2012
Last verified: August 2012
  Purpose

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 Intervention Phase
Heart Failure
Drug: Aliskiren 150 mg
Drug: Furosemide 60 mg
Drug: Placebo for Aliskiren
Drug: Aliskiren 300 mg
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Single Blind (Subject)
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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Diuretic Efficacy Index 1 for Sodium Excretion [ Time Frame: 0 to 4 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 to 24 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 to 4 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 to 24 hours ] [ Designated as safety issue: No ]
    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) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose ] [ Designated as safety issue: No ]

    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) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose ] [ Designated as safety issue: No ]
    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) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose ] [ Designated as safety issue: No ]
    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) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post dose ] [ Designated as safety issue: No ]
    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) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24 hours post dose ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose ] [ Designated as safety issue: No ]
    The renal clearance of drug [volume x time-1]

  • Creatinine Clearance [ Time Frame: 0 to 4, 4 to 8, 8 to 12 and 12 to 24 hours post dose ] [ Designated as safety issue: No ]
    Creatinine clearance= (Urine creatinine/Serum creatinine) x (Urine volume/(24*60)).

  • Urine Sodium and Potassium Excretion Per Treatment at 4 Hours Postdose [ Time Frame: 4 hours postdose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 8 hours postdose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 hours postdose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 24 hours postdose ] [ Designated as safety issue: No ]
    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) [ Time Frame: 0.5 hour pre-dose, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose. ] [ Designated as safety issue: No ]
    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.


Enrollment: 37
Study Start Date: May 2010
Study Completion Date: August 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01125514

Locations
Germany
Novartis Investigative Site
Berlin, Germany
Lithuania
Novartis Investigative Site
Vilnius, Lithuania
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01125514     History of Changes
Other Study ID Numbers: CSPP100A2255
Study First Received: May 17, 2010
Results First Received: August 9, 2012
Last Updated: August 9, 2012
Health Authority: Germany: Ministry of Health
Lithuania: State Medicine Control Agency - Ministry of Health

Keywords provided by Novartis:
Heart failure,
aliskiren,
furosemide,
diuretic efficacy,
interaction

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Furosemide
Sodium Potassium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 22, 2014