Placebo-Controlled Randomized Study of KW-3902 for Subjects Hospitalized With Worsening Renal Function and Heart Failure Requiring IV Therapy

Study Overview
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Brief Summary
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To evaluate the effect of KW-3902IV, in addition to standard therapy, on the proportion of worsening heart failure and worsening renal function, and on the proportion of deaths or rehospitalizations for heart failure or worsening renal function, and to estimate and compare within-trial medical resource utilization and direct medical costs between subjects treated with KW 3902IV versus placebo.

Detailed Description
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Loop diuretics are generally first line therapy in patients hospitalized with acute heart failure syndrome (AHFS). Their use far exceeds that of vasoactive agents. Tubuloglomerular feedback (TGF) is the body's compensatory response to avoid excess fluid loss, and it is activated when elevated sodium concentrations in the distal tubule are detected. TGF is proposed as a contributing factor for the observed diuretic resistance that occurs in patients with heart failure. Higher doses of diuretics are required to overcome the decreased natriuresis and reduced RBF induced by TGF. Ultimately, this action creates a vicious cycle of worsening renal function and diminished diuretic effectiveness. The primary pharmacologic rationale for the use of KW-3902 in subjects with AHFS is its mechanism of action as an adenosine A1 receptor antagonist. TGF promotes release of adenosine, and adenosine binding to A1 receptors causes vasoconstriction of the afferent arteriole, decreased RBF, and enhanced sodium reabsorption by the proximal tubule. This action results in a decrease in GFR, diminished renal function, and sodium and water retention. Blocking adenosine A1 receptors via a selective adenosine receptor antagonist may limit sodium reabsorption by the proximal tubules without triggering TGF. It promotes vasodilation of the afferent arteriole of the glomerulus, and thus, this strategy offers the potential to overcome diuretic resistance or enhance diuretic responsiveness. It may also reduce the need for increasing diuretic doses that have been associated with worse outcomes.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized With Worsening Renal Function and Heart Failure Requiring Intravenous Therapy

Conditions
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Heart Failure, Congestive

Intervention / Treatment
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* Drug: rolofylline
* Drug: Comparator: Placebo (unspecified)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Dyspnea at rest or with minimal exertion at randomization Fluid overload Estimated creatinine clearance (CrCl) between 20-60 mL/min Worsening renal function Anticipated need for IV diuretic treatment for at least 48 hours after the start of study drug BNP >500 pg/mL or NT-pro-BNP >2000 pg/mL Systolic blood pressure ≥90 mmHg at randomization Exclusion Criteria: IV radiographic contrast within 14 days IV vasodilators within 6 hours Serum potassium <3.5 meq/L Ongoing or planned therapy for heart failure with mechanical circulatory or ventilatory support Ongoing or planned treatment with ultrafiltration, hemofiltration, or dialysis Rapidly progressive acute renal failure Evidence of acute tubular necrosis or post-obstructive nephropathy or other exogenous causes of acute kidney injury, unrelated to heart failure Severe pulmonary disease Significant stenotic mitral or aortic valvular disease Heart transplant recipient or admitted for cardiac transplantation or LVAD surgery Any major surgery within 2 weeks prior evidence of acute coronary syndrome in the 2 weeks prior Hgb <8 g/dL, Hct <25%, or active bleeding requiring transfusion Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy. Known hepatic impairment Non-cardiac pulmonary edema Temperature >38°C Sepsis or active infection requiring IV anti-microbial treatment Administration of an investigational drug or device within 30 days Current or anticipated therapy with atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole Administration of any vasopressor or inotropic drug within 72 hours History of seizure (except febrile seizure) Stroke within 2 years History of brain tumor of any etiology Brain surgery within 2 years Encephalitis/meningitis within 2 years History of penetrating head trauma Closed head injury with loss of consciousness (LOC) over 30 minutes within 2 years History of or at risk for alcohol withdrawal seizures Advanced Alzheimer's disease Advanced multiple sclerosis

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 |
| --- | --- |
| Placebo Comparator: 2<br>placebo control | Drug: Comparator: Placebo (unspecified)<br>* rolofylline Pbo 30 mg IV QD; 3 days<br>|
| Experimental: 1<br>KW-3902IV | Drug: rolofylline<br>* rolofylline 30 mg IV QD; 3 days<br>* Other names: MK7418;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on heart failure signs and symptoms |  | through day 7 | 
| Effect on renal function |  | through Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, diuretic, renal impairment, renal function