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

NovaCardia, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Status and phase

Completed

Phase 3

Conditions

Heart Failure, Congestive

Treatments

Drug: Comparator: Placebo (unspecified)

Drug: rolofylline

Study type

Interventional

Funder types

Industry

Identifiers

NCT00443690

MK7418-303

CKI-303

2007_805

Details and patient eligibility

About

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.

Full description

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.

Enrollment

480 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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