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

October 8, 2009 updated by: NovaCardia, Inc.

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Actual)

932

Phase

  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 2
Drug: rolofylline
rolofylline 30 mg IV QD; 3 days
Other Names:
  • MK7418
  • KW-3902IV
Placebo Comparator: 1
Drug: Comparator: Placebo (unspecified)
rolofyline Pbo 30 mg IV QD; 3 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
effect on heart failure signs and symptoms
Time Frame: 3 days
3 days
effect on renal function
Time Frame: 3 days
3 days

Secondary Outcome Measures

Outcome Measure
Time Frame
safety
Time Frame: 3 days
3 days
within trial medical costs compared to placebo
Time Frame: 3 days
3 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NovaCardia, Inc.

Collaborators

Merck Sharp & Dohme LLC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2006

Primary Completion (Actual)

July 1, 2009

Study Completion (Actual)

July 1, 2009

Study Registration Dates

First Submitted

May 19, 2006

First Submitted That Met QC Criteria

May 19, 2006

First Posted (Estimate)

May 22, 2006

Study Record Updates

Last Update Posted (Estimate)

October 9, 2009

Last Update Submitted That Met QC Criteria

October 8, 2009

Last Verified

October 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CKI-301
  • 2007_803
  • MK7418-301

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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