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

Sponsors and Collaborators:	NovaCardia Merck
Information provided by:	NovaCardia
ClinicalTrials.gov Identifier:	NCT00443690

Purpose

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.

Condition	Intervention	Phase
Heart Failure, Congestive	Drug: rolofylline Drug: Comparator: Placebo (unspecified)	Phase III

MedlinePlus related topics: Heart Failure

Drug Information available for: 1,3-Dipropyl-8-(3-noradamantyl)xanthine

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study
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

Further study details as provided by NovaCardia:

Primary Outcome Measures:

Effect on heart failure signs and symptoms [ Time Frame: through day 7 ] [ Designated as safety issue: No ]
Effect on renal function [ Time Frame: through Day 7 ] [ Designated as safety issue: No ]

Estimated Enrollment:	480
Study Start Date:	August 2007
Estimated Study Completion Date:	June 2009
Estimated Primary Completion Date:	June 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
2: Placebo Comparator placebo control	Drug: Comparator: Placebo (unspecified) rolofylline Pbo 30 mg IV QD; 3 days
1: Experimental KW-3902IV	Drug: rolofylline rolofylline 30 mg IV QD; 3 days

Detailed 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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00443690

Contacts

Contact: Howard C Dittrich, MD	858.523.4505	howard_dittrich@merck.com
Contact: Gadi Cotter, MD		gadcotter@momentum-research.com

Show 49 Study Locations

Sponsors and Collaborators

NovaCardia

Merck

Investigators

Study Chair:	Barry Massie, MD	University of California San Francisco, USA
Study Chair:	Christopher O'Connor, MD	Duke University, USA

More Information

Responsible Party:	Merck & Co., Inc. ( Executive Vice President, Clinical and Quantitative Sciences )
Study ID Numbers:	CKI-303, 2007_805, MK7418-303
Study First Received:	March 2, 2007
Last Updated:	January 28, 2008
ClinicalTrials.gov Identifier:	NCT00443690
Health Authority:	United States: Food and Drug Administration; Germany: Federal Institute for Drugs and Medical Devices; Italy: Ministry of Health; Netherlands: Medicines Evaluation Board (MEB); Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products; Russia: Pharmacological Committee, Ministry of Health; United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by NovaCardia:

heart failure
diuretic
renal impairment
renal function

Study placed in the following topic categories:

Signs and Symptoms
Heart Failure
Heart Diseases
1,3-dipropyl-8-(3-noradamantyl)xanthine

Additional relevant MeSH terms:

Natriuretic Agents
Therapeutic Uses
Physiological Effects of Drugs
Diuretics

Cardiovascular Diseases
Cardiovascular Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 16, 2009