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 (Secret of CHF)

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

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Tolvaptan or Samsca; Drug: placebo or sugar pill

• Study Type: Interventional
• Enrollment (Actual): 250
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
    • Huntsville, Alabama, United States, 35801
      • The Heart Center Research
  • California
    • Los Angeles, California, United States, 90073
      • Greater Los Angeles VA Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health Science Ctr. Jacksonville
    • Melbourne, Florida, United States, 32901
      • MIMA Century Research Associates
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Augusta, Georgia, United States, 30901
      • University Cardiology Associates, LLC
    • Macon, Georgia, United States, 31201
      • Mercer University School of Medicine
  • Illinois
    • Naperville, Illinois, United States, 60540
      • Advocate Medical Group - Oakbrook
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Christ Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Medical Group
    • Munster, Indiana, United States, 46321
      • CardioSpecialists Group
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
    • Shreveport, Louisiana, United States, 71135
      • Advanced Cardiovascular Specialists
    • Slidell, Louisiana, United States, 70458
      • Louisiana Heart Center and Research
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center
  • Michigan
    • Rochester, Michigan, United States, 48307
      • Crittenton Hospital Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minneapolis Heart Institute
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Bryan Heart Institute
  • New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • The Valley Hospital
  • North Carolina
    • Gastonia, North Carolina, United States, 28054
      • Caromont Heart/Gaston Memorial Hospital
    • Lumberton, North Carolina, United States, 28358
      • Duke Cardiology of Lumberton Research/Southeastern Regional Medical Cente
  • Ohio
    • Akron, Ohio, United States, 44307
      • Akron General Medical Center
    • Cincinnatti, Ohio, United States, 45267
      • University of Cincinnati
    • Dayton, Ohio, United States, 45414
      • Dayton Heart Center
    • Fairfield, Ohio, United States, 45014
      • The Sisters of Mercy of Hamilton, Ohio dba Mercy Hospital Fairfield
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Oklahoma Heart Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College of Medicine
  • Rhode Island
    • Pawtucket, Rhode Island, United States, 02860
      • Memorial Hospital of RI
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hosptial
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center
    • Plano, Texas, United States, 75024
      • The Heart Hospital Baylor Plano - Research Insititute
  • Virginia
    • Lynchburg, Virginia, United States, 25401
      • CV Group Central Lynchburg/Stroobants Heart Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

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. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Tolvaptan, Samsca; Tolvaptan, Samsca, uncoated tablet, 30 mg, once per day, up to 7 days.	Drug: Tolvaptan or Samsca; uncoated tablet, 30mg, once per day, for up to 7 days.
PLACEBO_COMPARATOR: sugar pill; placebo, sugar pill	Drug: placebo or sugar pill; sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	8 and 16 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in body weight measured daily while hospitalized up to 7 days.	Change from baseline in body weight measured daily while hospitalized up to 7 days.	up to 7 days
Diuretic dose measured daily while hospitalized up to 7 days.	Diuretic dose measured daily while hospitalized up to 7 days.	up to 7 days.
Change from baseline in estimated glomerular filtration rate (eGFR) at discharge or day 7, whichever comes first.	Change from baseline in estimated glomerular filtration rate (eGFR) at discharge or day 7, whichever comes first.	at discharge or day 7, whichever comes first.
Days alive and out of the hospital over 30 days	Days alive and out of the hospital over 30 days	30 days.
Change from baseline in cognitive function at 48 hours or discharge, whichever comes first	Change from baseline in cognitive function at 48 hours or discharge, whichever comes first	at 48 hours or dischage, whichever comes first
Re-hospitalization for worsening heart failure or death at 30 days	Re-hospitalization for worsening heart failure or death at 30 days	30 days.

Collaborators and Investigators

• Sponsor: Cardiovascular Clinical Science Foundation
• Investigators: Principal Investigator: Marvin Konstam, MD, Cardiovascular Clinical Science Foundation

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (ACTUAL): July 1, 2016
• Study Completion (ACTUAL): August 1, 2016

Study Registration Dates

• First Submitted: April 10, 2012
• First Submitted That Met QC Criteria: April 23, 2012
• First Posted (ESTIMATE): April 25, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): September 27, 2016
• Last Update Submitted That Met QC Criteria: September 26, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: CCSF-2011-001