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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00354458
Recruitment Status : Completed
First Posted : July 20, 2006
Last Update Posted : October 9, 2009
Merck Sharp & Dohme Corp.
Information provided by:
NovaCardia, Inc.

Brief Summary:
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 or disease Intervention/treatment Phase
Heart Failure, Congestive Drug: rolofylline Drug: Comparator: Placebo (unspecified) Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, 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
Study Start Date : October 2006
Actual Primary Completion Date : July 2009
Actual Study Completion Date : July 2009

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
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:
  • KW-3902IV
  • MK7418

Primary Outcome Measures :
  1. effect on heart failure signs and symptoms [ Time Frame: 3 Days ]
  2. effect on renal function [ Time Frame: 3 Days ]

Secondary Outcome Measures :
  1. safety [ Time Frame: 3 Days ]
  2. within trial medical costs compared to placebo [ Time Frame: 3 Days ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 <500 pg/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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00354458

Sponsors and Collaborators
NovaCardia, Inc.
Merck Sharp & Dohme Corp.
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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
Publications automatically indexed to this study by Identifier (NCT Number):

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Responsible Party: Executive Vice President, Clinical and Quantitative Sciences, Merck & Co., Inc. Identifier: NCT00354458    
Other Study ID Numbers: CKI-302
First Posted: July 20, 2006    Key Record Dates
Last Update Posted: October 9, 2009
Last Verified: October 2009
Keywords provided by NovaCardia, Inc.:
heart failure
renal impairment
renal function
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Natriuretic Agents
Physiological Effects of Drugs