PROTECT-1: A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function - Full Text View

Sponsor:	NovaCardia, Inc.
Collaborator:	Merck
Information provided by:	NovaCardia, Inc.
ClinicalTrials.gov Identifier:	NCT00328692

Purpose

The study is being conducted to examine whether KW-3902IV will result in greater improvement in signs and symptoms of heart failure, with less treatment failure than standard therapy, when it is added to IV loop diuretics in subjects with acute heart failure syndrome and renal impairment.

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

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms and Renal Function in Subjects With Acute Heart Failure Syndrome and Renal Impairment Who Are Hospitalized for Volume Overload and Require Intravenous Diuretic Therapy

Resource links provided by NLM:

MedlinePlus related topics: Heart Failure

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

U.S. FDA Resources

Further study details as provided by NovaCardia, Inc.:

Primary Outcome Measures:

effect on heart failure signs and symptoms [ Time Frame: 3 days ] [ Designated as safety issue: No ]
effect on renal function [ Time Frame: 3 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

safety [ Time Frame: 3 days ] [ Designated as safety issue: Yes ]
within trial medical costs compared to placebo [ Time Frame: 3 days ] [ Designated as safety issue: No ]

Enrollment:	932
Study Start Date:	August 2006
Study Completion Date:	July 2009
Primary Completion Date:	July 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 2	Drug: rolofylline rolofylline 30 mg IV QD; 3 days Other Names: KW-3902IV MK7418
Placebo Comparator: 1	Drug: Comparator: Placebo (unspecified) rolofyline Pbo 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.

The objectives of this study are to evaluate the effect of KW-3902IV in addition to intravenous (IV) loop diuretics (such as furosemide) on heart failure signs and symptoms, renal function, and safety in subjects hospitalized with AHFS, volume overload, and renal impairment, and to estimate and compare within-trial medical resource utilization and direct medical costs between patients treated with KW-3902IV versus placebo.

Eligibility

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

Criteria

Inclusion Criteria:

History of heart failure of at least 14 days duration for which diuretic therapy has been prescribed
Hospitalized for acute heart failure syndrome requiring IV diuretic therapy.
Impaired renal function

Exclusion Criteria:

Acute contrast induced nephropathy
Ongoing or planned IV therapy for heart failure with positive inotropic agents, vasopressors, vasodilators, or mechanical support with the exception of IV nitrates
BNP <500pg/mL or NT-pro-BNP <2000 pg/mL
Ongoing or planned treatment with ultrafiltration, hemofiltration, or dialysis
Severe pulmonary disease
Significant stenotic valvular disease
Heart transplant recipient or admitted for cardiac transplantation
Clinical evidence of acute coronary syndrome in the 2 weeks prior to screening
Heart failure due to significant arrhythmias
Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy.
Known hepatic impairment
Non-cardiac pulmonary edema, including suspected sepsis
Allergy to soybean oil or eggs
History of seizure
Stroke within 2 years
History of or current 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
Hgb <8 g/dL, Hct <25%, or the need for a blood transfusion
Previous exposure to KW-3902

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00328692

Sponsors and Collaborators

NovaCardia, Inc.

Merck

Investigators

Study Chair:	Barry Massie, MD	University of California San Francisco, USA
Study Chair:	Christopher O'Connor, MD	Duke University, USA
Principal Investigator:	Marco Metra, MD	University of Brescia, Italy

More Information

No publications provided by NovaCardia, Inc.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

O'Connor CM, Fiuzat M, Lombardi C, Fujita K, Jia G, Davison BA, Cleland J, Bloomfield D, Dittrich HC, Delucca P, Givertz MM, Mansoor G, Ponikowski P, Teerlink JR, Voors AA, Massie BM, Cotter G, Metra M. Impact of serial troponin release on outcomes in patients with acute heart failure: analysis from the PROTECT pilot study. Circ Heart Fail. 2011 Nov 1;4(6):724-32. Epub 2011 Sep 6.

Voors AA, Dittrich HC, Massie BM, DeLucca P, Mansoor GA, Metra M, Cotter G, Weatherley BD, Ponikowski P, Teerlink JR, Cleland JG, O'Connor CM, Givertz MM. Effects of the adenosine A? receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective A? Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). J Am Coll Cardiol. 2011 May 10;57(19):1899-907.

Massie BM, O'Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, Weatherley BD, Cleland JG, Givertz MM, Voors A, DeLucca P, Mansoor GA, Salerno CM, Bloomfield DM, Dittrich HC; PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med. 2010 Oct 7;363(15):1419-28.

Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O'Connor CM, Metra M, Massie BM; Protect Steering Committee, Investigators, and Coordinators. The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail. 2008 Oct;14(8):631-40. Epub 2008 Sep 14.

Responsible Party:	Executive Vice President, Clinical and Quantitative Sciences, Merck & Co., Inc.
ClinicalTrials.gov Identifier:	NCT00328692 History of Changes
Other Study ID Numbers:	CKI-301, 2007_803, MK7418-301
Study First Received:	May 19, 2006
Last Updated:	October 8, 2009
Health Authority:	United States: Food and Drug Administration; Israel: Israeli Health Ministry Pharmaceutical Administration; Canada: Health Canada; Belgium: Directorate general for the protection of Public health: Medicines; Czech Republic: State Institute for Drug Control; Germany: Federal Institute for Drugs and Medical Devices; Hungary: National Institute of Pharmacy; 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

Keywords provided by NovaCardia, Inc.:

heart failure
diuretic
renal impairment
renal function

Additional relevant MeSH terms:

Heart Failure
Heart Diseases
Cardiovascular Diseases
Diuretics
1,3-dipropyl-8-(3-noradamantyl)xanthine
Purinergic P1 Receptor Antagonists
Natriuretic Agents
Physiological Effects of Drugs

Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on February 09, 2012