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NCT Number: NCT01125514

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

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.

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Key information

Conditions

Heart Failure Cardiovascular Diseases Heart Diseases

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Novartis Investigative Site, Berlin, Germany

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Aliskiren 150 mg

Drug

Aliskiren 150 mg tablet

Furosemide 60 mg

Drug

Furosemide 60 mg commercially-available tablets

Placebo for Aliskiren

Drug

Matching placebo for aliskiren 150 mg and 300 mg

Aliskiren 300 mg

Drug

Aliskiren 300 mg tablet

Primary outcomes

  1. Diuretic Efficacy Index 1 for Sodium Excretion

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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 outcomes

  1. 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

    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)

    Time frame: 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)

    Time frame: 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)

    Time frame: 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)

    Time frame: 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)

    Time frame: 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)

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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)

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study 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

Important dates

Study start
2010
Primary completion
2011
Study completion
2011
First posted
May 18, 2010
Registry last updated
Sep 10, 2012

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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