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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

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ClinicalTrials.gov Identifier: NCT00354458
Recruitment Status : Completed
First Posted : July 20, 2006
Last Update Posted : October 9, 2009
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by:
NovaCardia, Inc.

Tracking Information
First Submitted Date  ICMJE July 18, 2006
First Posted Date  ICMJE July 20, 2006
Last Update Posted Date October 9, 2009
Study Start Date  ICMJE October 2006
Actual Primary Completion Date July 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 28, 2008)
  • effect on heart failure signs and symptoms [ Time Frame: 3 Days ]
  • effect on renal function [ Time Frame: 3 Days ]
Original Primary Outcome Measures  ICMJE
 (submitted: July 18, 2006)
  • effect on heart failure signs and symptoms
  • effect on renal function
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 28, 2008)
  • safety [ Time Frame: 3 Days ]
  • within trial medical costs compared to placebo [ Time Frame: 3 Days ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2006)
  • safety
  • within trial medical costs compared to placebo
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure, Congestive
Intervention  ICMJE
  • Drug: rolofylline
    rolofylline 30 mg IV QD; 3 days
    Other Names:
    • KW-3902IV
    • MK7418
  • Drug: Comparator: Placebo (unspecified)
    rolofylline Pbo 30 mg IV QD; 3 days
Study Arms  ICMJE
  • Placebo Comparator: 1
    Intervention: Drug: Comparator: Placebo (unspecified)
  • Experimental: 2
    Intervention: Drug: rolofylline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 16, 2009)		 1102
Original Enrollment  ICMJE
 (submitted: July 18, 2006)		 920
Actual Study Completion Date  ICMJE July 2009
Actual Primary Completion Date July 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Belgium,   Czech Republic,   Denmark,   Finland,   France,   Germany,   Hungary,   Israel,   Italy,   Netherlands,   Poland,   Russian Federation,   Sweden,   United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT00354458
Other Study ID Numbers  ICMJE CKI-302
2007_804
MK7418-302
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Executive Vice President, Clinical and Quantitative Sciences, Merck & Co., Inc.
Original Responsible Party Not Provided
Current Study Sponsor  ICMJE NovaCardia, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Merck Sharp & Dohme LLC
Investigators  ICMJE
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
PRS Account NovaCardia, Inc.
Verification Date October 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP