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

Heart Failure, Congestive Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00354458
• Other study ID #: CKI-302
• Secondary ID: 2007_804MK7418-3
• Status: Completed
• Phase: Phase 3
• First received: July 18, 2006
• Last updated: October 8, 2009
• Start date: October 2006
• Est. completion date: July 2009

Study information

• Verified date: October 2009
• Source: NovaCardia, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Czech Republic: State Institute for Drug ControlDenmark: Danish Medicines AgencyFinland: Finnish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of PharmacyIsrael: Israeli Health Ministry Pharmaceutical AdministrationItaly: Ministry of HealthNetherlands: Medicines Evaluation Board (MEB)Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsSweden: Medical Products AgencyRussia: Pharmacological Committee, Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1102
• Est. completion date: July 2009
• Est. primary completion date: July 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Congestive

Intervention

Drug:
• rolofylline
rolofylline 30 mg IV QD; 3 days
• Comparator: Placebo (unspecified)
rolofylline Pbo 30 mg IV QD; 3 days

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
NovaCardia, Inc.	Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	effect on heart failure signs and symptoms		3 Days	No
Primary	effect on renal function		3 Days	No
Secondary	safety		3 Days	Yes
Secondary	within trial medical costs compared to placebo		3 Days	No