PROTECT-2: 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
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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 3 |
| 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 |
- 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 ]
- 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: | 1102 |
| Study Start Date: | October 2006 |
| Study Completion Date: | July 2009 |
| Primary Completion Date: | July 2009 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Placebo Comparator: 1 |
Drug: Comparator: Placebo (unspecified)
rolofylline Pbo 30 mg IV QD; 3 days
|
| Experimental: 2 |
Drug: rolofylline
rolofylline 30 mg IV QD; 3 days
Other Names:
|
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 |
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 <500 pg/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| 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):
| Responsible Party: | Executive Vice President, Clinical and Quantitative Sciences, Merck & Co., Inc. |
| ClinicalTrials.gov Identifier: | NCT00354458 History of Changes |
| Other Study ID Numbers: | CKI-302, 2007_804, MK7418-302 |
| Study First Received: | July 18, 2006 |
| Last Updated: | October 8, 2009 |
| Health Authority: | Czech Republic: State Institute for Drug Control Denmark: Danish Medicines Agency Finland: Finnish Medicines Agency France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Germany: Federal Institute for Drugs and Medical Devices Hungary: National Institute of Pharmacy Israel: Israeli Health Ministry Pharmaceutical Administration Italy: Ministry of Health Netherlands: Medicines Evaluation Board (MEB) Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Sweden: Medical Products Agency Russia: Pharmacological Committee, Ministry of Health United Kingdom: Medicines and Healthcare Products Regulatory Agency United States: Food and Drug Administration |
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 May 21, 2013