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

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by:
NovaCardia, Inc.
ClinicalTrials.gov Identifier:
NCT00328692
First received: May 19, 2006
Last updated: October 8, 2009
Last verified: October 2009
  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

Resource links provided by NLM:


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:

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

Exclusion Criteria:

  1. Acute contrast induced nephropathy
  2. Ongoing or planned IV therapy for heart failure with positive inotropic agents, vasopressors, vasodilators, or mechanical support with the exception of IV nitrates
  3. BNP <500pg/mL or NT-pro-BNP <2000 pg/mL
  4. Ongoing or planned treatment with ultrafiltration, hemofiltration, or dialysis
  5. Severe pulmonary disease
  6. Significant stenotic valvular disease
  7. Heart transplant recipient or admitted for cardiac transplantation
  8. Clinical evidence of acute coronary syndrome in the 2 weeks prior to screening
  9. Heart failure due to significant arrhythmias
  10. Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy.
  11. Known hepatic impairment
  12. Non-cardiac pulmonary edema, including suspected sepsis
  13. Allergy to soybean oil or eggs
  14. History of seizure
  15. Stroke within 2 years
  16. History of or current brain tumor of any etiology
  17. Brain surgery within 2 years
  18. Encephalitis/meningitis within 2 years
  19. History of penetrating head trauma
  20. Closed head injury with loss of consciousness (LOC) over 30 minutes within 2 years
  21. History of, or at risk for, alcohol withdrawal seizures
  22. Advanced Alzheimer's disease
  23. Advanced multiple sclerosis
  24. Hgb <8 g/dL, Hct <25%, or the need for a blood transfusion
  25. Previous exposure to KW-3902
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Sponsors and Collaborators
NovaCardia, Inc.
Merck Sharp & Dohme Corp.
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):

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: Federal Agency for Medicines and Health Products, FAMHP
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
Renal Insufficiency
Heart Diseases
Cardiovascular Diseases
Kidney Diseases
Urologic 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 August 28, 2014