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
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
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
NCT ID
NCT00443690
First Posted
March 2, 2007
Last Updated
February 19, 2009
Sponsor
NovaCardia, Inc.
Collaborators
Merck Sharp & Dohme LLC
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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