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

Heart Failure, Congestive Clinical Trial

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Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00443690
• Other study ID #: CKI-303
• Secondary ID: 2007_805MK7418-3
• Status: Completed
• Phase: Phase 3
• First received: March 2, 2007
• Last updated: February 19, 2009
• Start date: August 2007
• Est. completion date: January 2009

Study information

• Verified date: February 2009
• Source: NovaCardia, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationGermany: Federal Institute for Drugs and Medical DevicesItaly: Ministry of HealthNetherlands: Medicines Evaluation Board (MEB)Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRussia: Pharmacological Committee, Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 480
• Est. completion date: January 2009
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Congestive

Intervention

Drug:
• rolofylline
rolofylline 30 mg IV QD; 3 days
• Comparator: Placebo (unspecified)
rolofylline Pbo 30 mg IV QD; 3 days

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
NovaCardia, Inc.	Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effect on heart failure signs and symptoms		through day 7	No
Primary	Effect on renal function		through Day 7	No