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

Condition(s) targeted: Heart Failure, Congestive

Intervention: rolofylline (Drug); Comparator: Placebo (unspecified) (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: NovaCardia

Official(s) and/or principal investigator(s):
Barry Massie, MD, Study Chair, Affiliation: University of California San Francisco, USA
Christopher O'Connor, MD, Study Chair, Affiliation: Duke University, USA
Marco Metra, MD, Principal Investigator, Affiliation: University of Brescia, Italy

Overall contact:
Howard C Dittrich, MD, Phone: 858.523.4505, Email: howard_dittrich@merck.com

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.

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 design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome:

effect on heart failure signs and symptoms

effect on renal function

Secondary outcome:

safety

within trial medical costs compared to placebo

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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 <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

Howard C Dittrich, MD, Phone: 858.523.4505, Email: howard_dittrich@merck.com

Brno, Czech Republic; Recruiting

Praha, Czech Republic; Recruiting

Copenhagen, Denmark; Recruiting

Hellerup, Denmark; Recruiting

Silkeborg, Denmark; Recruiting

Helsinki, Finland; Recruiting

Jyvaskyla, Finland; Recruiting

Pontoise, France; Recruiting

Toulouse, France; Recruiting

Paris, France; Recruiting

Marseille, France; Recruiting

Nantes, France; Not yet recruiting

Homburg / Saar, Germany; Recruiting

Bad Nauheim, Germany; Recruiting

Halle / Saale, Germany; Recruiting

Herford, Germany; Recruiting

Greifswald, Germany; Recruiting

Szeged, Hungary; Recruiting

Budapest, Hungary; Recruiting

Nazareth, Israel; Recruiting

Jerusalem, Israel; Recruiting

Haifa, Israel; Recruiting

Tel-Hashomer, Israel; Not yet recruiting

Holon, Israel; Not yet recruiting

Ashkelon, Israel; Not yet recruiting

Rehovot, Israel; Not yet recruiting

Brescia, Italy; Recruiting

Amsterdam, Netherlands; Recruiting

Groningen, Netherlands; Recruiting

Delft, Netherlands; Recruiting

Alkmaar, Netherlands; Recruiting

Wroclaw, Poland; Recruiting

Lodz, Poland; Recruiting

Walbrzych, Poland; Recruiting

Warszawa, Poland; Recruiting

Katowice, Poland; Not yet recruiting

Ziolowa, Poland; Recruiting

Moscow, Russian Federation; Recruiting

St. Petersburg, Russian Federation; Recruiting

Linkoping, Sweden; Not yet recruiting

Gothenburg, Sweden; Not yet recruiting

Stockholm, Sweden; Not yet recruiting

Vasteras, Sweden; Not yet recruiting

Cottingham, United Kingdom; Recruiting

Middlesex, United Kingdom; Recruiting

Leicestershire, United Kingdom; Recruiting

North Yorkshire, United Kingdom; Recruiting

Birmingham West Midlands, United Kingdom; Recruiting

Warwickshire, United Kingdom; Recruiting

Torrance, California, United States; Not yet recruiting

San Diego, California, United States; Recruiting

Los Angeles, California, United States; Recruiting

Palo Alto, California, United States; Not yet recruiting

La Jolla, California, United States; Not yet recruiting

Sylmar, California, United States; Recruiting

New Haven, Connecticut, United States; Not yet recruiting

Jacksonville, Florida, United States; Not yet recruiting

Chicago, Illinois, United States; Not yet recruiting

Ayer, Massachusetts, United States; Recruiting

Detroit, Michigan, United States; Not yet recruiting

Camden, New Jersey, United States; Not yet recruiting

Durham, North Carolina, United States; Not yet recruiting

Greensboro, North Carolina, United States; Recruiting

Cleveland, Ohio, United States; Not yet recruiting

Pittsburgh, Pennsylvania, United States; Recruiting

Philadelphia, Pennsylvania, United States; Not yet recruiting

Memphis, Tennessee, United States; Not yet recruiting

Germantown, Tennessee, United States; Recruiting

Amarillo, Texas, United States; Recruiting

Roanoke, Virginia, United States; Not yet recruiting

Kirkland, Washington, United States; Recruiting

Starting date: October 2006
Ending date: November 2008
Last updated: January 28, 2008