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Placebo-Controlled Randomized Study of KW-3902 for Subjects Hospitalized With Worsening Renal Function and Heart Failure Requiring IV Therapy (REACH UP)

Primary Purpose

Heart Failure, Congestive

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
rolofylline
Comparator: Placebo (unspecified)
Sponsored by
NovaCardia, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure, Congestive focused on measuring heart failure, diuretic, renal impairment, renal function

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Dyspnea at rest or with minimal exertion at randomization
  • Fluid overload
  • Estimated creatinine clearance (CrCl) between 20-60 mL/min
  • Worsening renal function
  • Anticipated need for IV diuretic treatment for at least 48 hours after the start of study drug
  • BNP >500 pg/mL or NT-pro-BNP >2000 pg/mL
  • Systolic blood pressure ≥90 mmHg at randomization

Exclusion Criteria:

  • IV radiographic contrast within 14 days
  • IV vasodilators within 6 hours
  • Serum potassium <3.5 meq/L
  • Ongoing or planned therapy for heart failure with mechanical circulatory or ventilatory support
  • Ongoing or planned treatment with ultrafiltration, hemofiltration, or dialysis
  • Rapidly progressive acute renal failure
  • Evidence of acute tubular necrosis or post-obstructive nephropathy or other exogenous causes of acute kidney injury, unrelated to heart failure
  • Severe pulmonary disease
  • Significant stenotic mitral or aortic valvular disease
  • Heart transplant recipient or admitted for cardiac transplantation or LVAD surgery
  • Any major surgery within 2 weeks prior
  • evidence of acute coronary syndrome in the 2 weeks prior
  • Hgb <8 g/dL, Hct <25%, or active bleeding requiring transfusion
  • Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy.
  • Known hepatic impairment
  • Non-cardiac pulmonary edema
  • Temperature >38°C
  • Sepsis or active infection requiring IV anti-microbial treatment
  • Administration of an investigational drug or device within 30 days
  • Current or anticipated therapy with atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole
  • Administration of any vasopressor or inotropic drug within 72 hours
  • History of seizure (except febrile seizure)
  • Stroke within 2 years
  • History of brain tumor of any etiology
  • Brain surgery within 2 years
  • Encephalitis/meningitis within 2 years
  • History of penetrating head trauma
  • Closed head injury with loss of consciousness (LOC) over 30 minutes within 2 years
  • History of or at risk for alcohol withdrawal seizures
  • Advanced Alzheimer's disease
  • Advanced multiple sclerosis

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Placebo Comparator

    Experimental

    Arm Label

    2

    1

    Arm Description

    placebo control

    KW-3902IV

    Outcomes

    Primary Outcome Measures

    Effect on heart failure signs and symptoms
    Effect on renal function

    Secondary Outcome Measures

    Full Information

    First Posted
    March 2, 2007
    Last Updated
    February 19, 2009
    Sponsor
    NovaCardia, Inc.
    Collaborators
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00443690
    Brief Title
    Placebo-Controlled Randomized Study of KW-3902 for Subjects Hospitalized With Worsening Renal Function and Heart Failure Requiring IV Therapy
    Acronym
    REACH UP
    Official Title
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized With Worsening Renal Function and Heart Failure Requiring Intravenous Therapy
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    February 2009
    Overall Recruitment Status
    Completed
    Study Start Date
    August 2007 (undefined)
    Primary Completion Date
    January 2009 (Actual)
    Study Completion Date
    January 2009 (Actual)

    3. Sponsor/Collaborators

    Name of the Sponsor
    NovaCardia, Inc.
    Collaborators
    Merck Sharp & Dohme LLC

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    To evaluate the effect of KW-3902IV, in addition to standard therapy, on the proportion of worsening heart failure and worsening renal function, and on the proportion of deaths or rehospitalizations for heart failure or worsening renal function, and to estimate and compare within-trial medical resource utilization and direct medical costs between subjects treated with KW 3902IV versus 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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Heart Failure, Congestive
    Keywords
    heart failure, diuretic, renal impairment, renal function

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    480 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    2
    Arm Type
    Placebo Comparator
    Arm Description
    placebo control
    Arm Title
    1
    Arm Type
    Experimental
    Arm Description
    KW-3902IV
    Intervention Type
    Drug
    Intervention Name(s)
    rolofylline
    Other Intervention Name(s)
    KW-3902IV, MK7418
    Intervention Description
    rolofylline 30 mg IV QD; 3 days
    Intervention Type
    Drug
    Intervention Name(s)
    Comparator: Placebo (unspecified)
    Intervention Description
    rolofylline Pbo 30 mg IV QD; 3 days
    Primary Outcome Measure Information:
    Title
    Effect on heart failure signs and symptoms
    Time Frame
    through day 7
    Title
    Effect on renal function
    Time Frame
    through Day 7

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Dyspnea at rest or with minimal exertion at randomization Fluid overload Estimated creatinine clearance (CrCl) between 20-60 mL/min Worsening renal function Anticipated need for IV diuretic treatment for at least 48 hours after the start of study drug BNP >500 pg/mL or NT-pro-BNP >2000 pg/mL Systolic blood pressure ≥90 mmHg at randomization Exclusion Criteria: IV radiographic contrast within 14 days IV vasodilators within 6 hours Serum potassium <3.5 meq/L Ongoing or planned therapy for heart failure with mechanical circulatory or ventilatory support Ongoing or planned treatment with ultrafiltration, hemofiltration, or dialysis Rapidly progressive acute renal failure Evidence of acute tubular necrosis or post-obstructive nephropathy or other exogenous causes of acute kidney injury, unrelated to heart failure Severe pulmonary disease Significant stenotic mitral or aortic valvular disease Heart transplant recipient or admitted for cardiac transplantation or LVAD surgery Any major surgery within 2 weeks prior evidence of acute coronary syndrome in the 2 weeks prior Hgb <8 g/dL, Hct <25%, or active bleeding requiring transfusion Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy. Known hepatic impairment Non-cardiac pulmonary edema Temperature >38°C Sepsis or active infection requiring IV anti-microbial treatment Administration of an investigational drug or device within 30 days Current or anticipated therapy with atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole Administration of any vasopressor or inotropic drug within 72 hours History of seizure (except febrile seizure) Stroke within 2 years History of brain tumor of any etiology Brain surgery within 2 years Encephalitis/meningitis within 2 years History of penetrating head trauma Closed head injury with loss of consciousness (LOC) over 30 minutes within 2 years History of or at risk for alcohol withdrawal seizures Advanced Alzheimer's disease Advanced multiple sclerosis
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Barry Massie, MD
    Organizational Affiliation
    University of California San Francisco, USA
    Official's Role
    Study Chair
    First Name & Middle Initial & Last Name & Degree
    Christopher O'Connor, MD
    Organizational Affiliation
    Duke University, USA
    Official's Role
    Study Chair

    12. IPD Sharing Statement

    Learn more about this trial

    Placebo-Controlled Randomized Study of KW-3902 for Subjects Hospitalized With Worsening Renal Function and Heart Failure Requiring IV Therapy

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