Clinical trial NCT01584557: Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management
Official title: A Phase 3 Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Failure
Lead sponsor: Cardiovascular Clinical Sciences Inc
Sponsor class: INDUSTRY
First posted: 2012-04-25
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the short term efficacy and safety of tolvaptan in subjects hospitalized for worsening heart failure who have volume overload and one of the following: renal insufficiency, or hyponatremia or inadequate response to diuretic therapy. The primary variable for assessing efficacy will be self-assessed 7-point dyspnea score at 8 and 16 hours.


Eligibility criteria: Inclusion Criteria:

1. Subjects hospitalized for worsening heart failure and randomized within 36 hours of initial presentation.
2. Males and females 18 years of age or older.
3. NYHA Class III or IV on admission to the hospital.
4. Able to understand content of and willing to provide written informed consent
5. Dyspnea, measured by the 5-point current dyspnea scale (moderately short of breath or worse), within 2 hours of randomization and dosing.

   The following must be met within 12 hours of randomization.
6. The subject must have signs of extracellular volume expansion, defined as two or more of the following five: Signs of RHF ( jugular venous distention, pitting edema (≥1+), ascites) and/or Signs of LHF (pulmonary congestion on chest x-ray, pulmonary rales)
7. Have at least one of the following:

   * eGFR \< 60ml/min/1.73m2, OR
   * serum sodium ≤ 134 mEq/L, OR
   * urine output ≤ 125 ml/hr over anytime frame of at least 2 hours, following administration of IV furosemide of at least 40mg. See table below.

Time Period (hr) Cumulative UO (mL) 2 \<250 3 \<375 4 \<500 5 \<625 6 \<750 7 \<875 8 \<1000

Exclusion Criteria:

1. Positive urine pregnancy test for women of child bearing potential.
2. Inability to provide written informed consent.
3. Cardiac surgery within 60 days prior to study randomization.
4. Acute Coronary Syndrome (ACS) or percutaneous coronary intervention within 30 days prior to study randomization.
5. Planned revascularization procedures, cardiac mechanical support implantation, cardiac transplantation, or other cardiac surgery within 30 days following study randomization.
6. Planned electrophysiologic (EP) device implantation within 7 days following study randomization.
7. Subjects who are on cardiac mechanical support.
8. Co-morbid condition with an expected survival less than six months.
9. History of a cerebrovascular accident within the last 30 days.
10. Hemodynamically significant uncorrected primary cardiac valvular disease.
11. Hypertrophic cardiomyopathy (obstructive or non-obstructive).
12. Uncorrected thyroid disease, active myocarditis or known amyloid cardiomyopathy.
13. History of primary significant liver disease or acute hepatic failure, as defined by the investigator.
14. Chronic uncontrolled diabetes mellitus as determined by the investigator.
15. Supine systolic arterial blood pressure \< 90 mmHg.
16. Serum creatinine \> 3.5 mg/dL or undergoing dialysis.
17. Hemoglobin \< 9 g/dL
18. History of hypersensitivity and/or idiosyncratic reaction to benzazepine derivatives (such as benazepril).
19. Inability to take oral medications.
20. Participation in another clinical drug or device trial where the last dose of drug was within the past 30 days or an investigational medical device is currently implanted.
21. Previous exposure to tolvaptan within 7 days prior to randomization.
22. Subjects with refractory, end-stage, heart failure defined as subjects who are appropriate candidates for specialized treatment strategies, such as ventricular assist devices, continuous positive IV inotropic therapy, or hospice care.
23. Ultrafiltration within 7 days prior to randomization or planned.
24. Active gout
25. Serum sodium \>144 mEq/L

Primary outcomes:
measure: To evaluate the short term efficacy and safety of tolvaptan in subjects hospitalized for worsening heart failure who have volume overload and one of the following: renal insufficiency, or hyponatremia or inadequate response to diuretic therapy.
timeFrame: 8 and 16 hours
Secondary outcomes:
measure: Change from baseline in body weight measured daily while hospitalized up to 7 days.
timeFrame: up to 7 days
measure: Diuretic dose measured daily while hospitalized up to 7 days.
timeFrame: up to 7 days.
measure: Change from baseline in estimated glomerular filtration rate (eGFR) at discharge or day 7, whichever comes first.
timeFrame: at discharge or day 7, whichever comes first.
measure: Days alive and out of the hospital over 30 days
timeFrame: 30 days.
measure: Change from baseline in cognitive function at 48 hours or discharge, whichever comes first
timeFrame: at 48 hours or dischage, whichever comes first
measure: Re-hospitalization for worsening heart failure or death at 30 days
timeFrame: 30 days.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Huntsville
country: United States
facility: The Heart Center Research
state: Alabama
city: Los Angeles
country: United States
facility: Greater Los Angeles VA Medical Center
state: California
city: Jacksonville
country: United States
facility: University of Florida Health Science Ctr. Jacksonville
state: Florida
city: Melbourne
country: United States
facility: MIMA Century Research Associates
state: Florida
city: Miami
country: United States
facility: Jackson Memorial Hospital
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Augusta
country: United States
facility: University Cardiology Associates, LLC
state: Georgia
city: Macon
country: United States
facility: Mercer University School of Medicine
state: Georgia
city: Naperville
country: United States
facility: Advocate Medical Group - Oakbrook
state: Illinois
city: Oak Lawn
country: United States
facility: Advocate Christ Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: St. Vincent Medical Group
state: Indiana
city: Munster
country: United States
facility: CardioSpecialists Group
state: Indiana
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Shreveport
country: United States
facility: Advanced Cardiovascular Specialists
state: Louisiana
city: Slidell
country: United States
facility: Louisiana Heart Center and Research
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Hospital and Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Crittenton Hospital Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute
state: Minnesota
city: Lincoln
country: United States
facility: Bryan Heart Institute
state: Nebraska
city: Ridgewood
country: United States
facility: The Valley Hospital
state: New Jersey
city: Gastonia
country: United States
facility: Caromont Heart/Gaston Memorial Hospital
state: North Carolina
city: Lumberton
country: United States
facility: Duke Cardiology of Lumberton Research/Southeastern Regional Medical Cente
state: North Carolina
city: Akron
country: United States
facility: Akron General Medical Center
state: Ohio
city: Cincinnatti
country: United States
facility: University of Cincinnati
state: Ohio
city: Dayton
country: United States
facility: Dayton Heart Center
state: Ohio
city: Fairfield
country: United States
facility: The Sisters of Mercy of Hamilton, Ohio dba Mercy Hospital Fairfield
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma Heart Hospital
state: Oklahoma
city: Philadelphia
country: United States
facility: Drexel University College of Medicine
state: Pennsylvania
city: Pawtucket
country: United States
facility: Memorial Hospital of RI
state: Rhode Island
city: Providence
country: United States
facility: The Miriam Hosptial
state: Rhode Island
city: Houston
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Plano
country: United States
facility: The Heart Hospital Baylor Plano - Research Insititute
state: Texas
city: Lynchburg
country: United States
facility: CV Group Central Lynchburg/Stroobants Heart Center
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Cardiovascular Clinical Sciences Inc
name: Marvin Konstam, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Konstam MA, Kiernan M, Chandler A, Dhingra R, Mody FV, Eisen H, Haught WH, Wagoner L, Gupta D, Patten R, Gordon P, Korr K, Fileccia R, Pressler SJ, Gregory D, Wedge P, Dowling D, Romeling M, Konstam JM, Massaro JM, Udelson JE; SECRET of CHF Investigators, Coordinators, and Committee Members. Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload. J Am Coll Cardiol. 2017 Mar 21;69(11):1409-1419. doi: 10.1016/j.jacc.2016.12.035.