Renal Hemodynamic Effects of RLX030A in Subjects With Chronic Heart Failure (CHF)

Study Overview
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Brief Summary
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This study will assess the renal hemodynamic effect of RLX030 infusion in subjects with chronic heart failure. In addition safety and effects on renal function and biomarkers will be assessed.

Official Title
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A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Study to Evaluate the Renal Hemodynamic Effects of RLX030 and Placebo Infused for 24 Hours in Subjects With Chronic Heart Failure (CHF)

Conditions
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Chronic Heart Failure (CHF)

Intervention / Treatment
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* Drug: RLX030
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained before any assessment is performed. Male and female heart failure patients with body weight <160 kg, on standard therapy including a stable dose of furosemide 40-240 mg/day orally (p.o). or equivalent dose of loop diuretics, reduced systolic function (LVEF ≤ 45% measured within the past 6 months), BNP ≥ 100 pg/mL or NT-pro-BNP of ≥ 400 pg/mLNYHA Class II or III, and worsening symptoms, e.g. fatigue, dyspnea, breathlessness within 3 months Mild to moderate renal impairment Exclusion criteria: Systolic blood pressure (SBP) < 110 mm Hg at the time of randomization Administration of intravenous radiographic contrast agent within 72 hours prior to randomization or acute contrast-induced nephropathy at the time of randomization Current use of non-steroidal antiinflammatory drugs (NSAIDs) Current or planned (through the completion of study drug infusion) treatment with any i.v. therapies, including vasodilators (including nesiritide), positive inotropic agents, vasopressors, levosimendan, or mechanical support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device). Clinically significant hepatic impairment defined as hepatic encephalopathy of any degree or total bilirubin > 50 μmol/l (3 mg/dl) or, if patient is not on warfarin therapy, INR > 2.0 (or Prothrombin Time > 2 * ULN) Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RLX030<br>RLX030 as intravenous infusion for 24 hours. | Drug: RLX030<br>* RLX030 as intravenous infusion for 24 hours.<br>|
| Placebo Comparator: Placebo<br>Placebo as intravenous infusion for 24 hours. | Drug: Placebo<br>* Intravenous infusion of Placebo over 24 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in renal plasma flow (RPF) measured by Para-aminohippuric acid (PAH) clearance in subjects with CHF after 24 hours intravenous (i.v) infusion of RLX030 | Serial blood and urine collections over time for determination of PAH and its clearance respectively | Baseline, during and after the end of 24 hours infusion | 
| Change from baseline in glomerular filtration rate (GFR) as measured by Iothalamate (IOTH) clearance in subjects with CHF after 24 hours i.v. infusion of RLX030 | Serial blood and urine collections over time for determination of IOTH and its clearance respectively | Baseline, during and after the end of 24 hours infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in filtration fraction (FF) in subjects with CHF after 24 hours infusion of RLX030 | The filtration fraction (FF) is derived as the ratio of GFR divided by RBF in percent. | Baseline, during and after the end of 24 hours of infusion | 
| Change over time in Diuresis | Urine samples will be collected for analyses. | During 24 hours of infusion and after the end of the infusion | 
| Change over time in calculated creatinine clearance | Urine samples will be collected for analyses. | During 24 hours of infusion and after the end of the infusion | 
| Change over time on fractional sodium excretion(natriuresis) | Urine samples will be collected for analyses. | During 24 hours of infusion and after the end of the infusion | 
| Central aortic systolic pressure-time curve | A cuff will be used for a brachial blood pressure measurement and a wrist sensor for arterial pulse waveforms | During 24 hours of infusion and after the end of the infusion | 
| Radial augmentation index-time curve | A cuff will be used for a brachial blood pressure measurement and a wrist sensor for arterial pulse waveforms | During 24 hours of infusion and after the end of the infusion | 
| Number of patients with adverse events, serious adverse events and death | Monitoring of adverse events, serious adverse events and death from screening to end of study | During 24 hours of infusion and after the end of the infusion | 
| Pharmacokinetics of RLX030: area under the serum concentration-time curve from time zero to infinity (AUCinf)Time | Blood will be collected from an indwelling catheter. | During 24 hours of infusion and for 24 hours after the end of infusion | 
| Pharmacokinetics of RLX030: area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) | Blood will be collected from an indwelling catheter. | During 24 hours of infusion and for 24 hours after the end of infusion | 
| Pharmacokinetics of RLX030: serum concentration over 20 hours of infusion (C24h) | Blood will be collected from an indwelling catheter. | During 24 hours of infusion and for 24 hours after the end of infusion | 
| Pharmacokinetics of RLX030: terminal elimination half-life (T1/2)following intravenous administration | Blood will be collected from an indwelling catheter. | During 24 hours of infusion and for 24 hours after the end of infusion | 
| Pharmacokinetics of RLX030: mean residence time (MRT)intravenous administration | Blood will be collected from an indwelling catheter. | During 24 hours of infusion and for 24 hours after the end of infusion | 
| Pharmacokinetics of RLX030: volume of distribution at steady state (Vss) following intravenous administration | Blood will be collected from an indwelling catheter. | During 24 hours of infusion and for 24 hours after the end of infusion | 
| Pharmacokinetics of RLX030: systemic clearance from serum (CL) following intravenous administration(natriuresis) | Blood will be collected from an indwelling catheter. | During 24 hours of infusion and for 24 hours after the end of infusion | 
| Corrected QT (QTc) Interval Using Fridericia's and Bazett's Formula | Continuous 12 lead Holter ECG monitoring for extraction of ECGs and analysis | Baseline, during the 24 hours of infusion and after the end of the infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure, hemodynamics, cardiovascular diseases, RLX030