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The primary objective of this study is to compare the effects of oral Tolvaptan vs. placebo as an adjunct to fixed dose IV furosemide on dyspnea relief in patients with acute decompensated heart failure
The primary hypothesis is that the addition of oral Tolvaptan to fixed dose furosemide will be more effective at relieving dyspnea than fixed dose furosemide alone
This study will be a randomized, double blind, placebo controlled, multi-center clinical trial of patients with signs and symptoms consistent with AHF within 24 hours of presentation at Emergency Department. A total of approximately 250 patients will be enrolled in the trial.
Patients will be randomized in a 1:1 ratio to either of 2 treatment regimens:
The study treatment regimen will be administered from randomization through 48 hours, at which point Tolvaptan/placebo will be discontinued and all diuretic treatment will be adjusted at the treating physician's discretion.
The primary endpoint will be the proportion of patients with at least moderate improvement in dyspnea by Likert scale at both 8 AND 24 hours AND without the need for escalation of therapy due to worsening heart failure (rescue therapy) or death within 24 hours.
Patients will be followed daily for the duration of hospitalization or for 7 days (whichever is shortest).
All patients will have Day 30 follow up phone contact for assessment of vital status and interval hospitalizations.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tolvaptan | Experimental | Fixed-dose IV furosemide (1 x total daily oral dose given intravenously in divided doses Q12 hours OR 40 mg IV Q12 hours, whichever is greater) + oral Tolvaptan (given at 0, 24 and 48 hours) |
|
| Placebo | Placebo Comparator | Fixed-dose IV furosemide (1 x total daily oral dose given intravenously in divided doses Q12 hours OR 40 mg IV Q12 hours, whichever is greater) + oral placebo (given at 0, 24 and 48 hours) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tolvaptan | Drug | IV furosemide plusTolvaptan (given at 0, 24 and 48 hours) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours | The number of patients with at least moderate improvement (as reported by patient) in dyspnea Likert scale at both 8 AND 24 hours AND without the need for escalation of therapy due to worsening heart failure (rescue therapy) or death within 24 hours. | 8 and 24 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Renal Function | Change in Serum creatinine from baseline to 24, 48 and 72 hours | 0, 24, 48 and 72 hours |
| Weight Loss | Change in body weight from baseline to 24, 48, and 72 hours |
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Inclusion Criteria:
≥ 18 years of age
Daily oral dose of furosemide between ≥ 40 mg(or equivalent)
Identified within 24 hours of presentation, defined for purposes of this study as the time of initial dose of intravenous loop diuretic
Prior clinical HF diagnosis that was treated with oral loop diuretics for at least 1 month
Admission for acute decompensated Heart Failure (HF) as determined by
AND at least one of the following additional signs and symptoms:
Exclusion Criteria:
Serum Na > 140 meq/L
Received IV vasoactive treatment or ultra-filtration therapy for HF since initial presentation
Treatment plan during current hospitalization includes IV vasoactive treatment or ultra-filtration for HF
Systolic Blood Pressure (SBP)<90mmHg
Serum-Cr>3.5mg/dl or currently undergoing renal replacement therapy
. Known underlying liver disease
Hemodynamically significant arrhythmias
ACS(Acute coronary syndrome) within 4 weeks prior to study entry
Active myocarditis
Hypertrophic obstructive, restrictive, constrictive cardiomyopathy
Severe stenotic valvular disease
Complex congenital heart disease
Constrictive pericarditis
Clinical evidence of digoxin toxicity
Need for mechanical hemodynamic support
Terminal illness (other than heart failure) with expected survival time of less than 1 year
History of adverse reaction to Tolvaptan
Enrollment or planned enrollment in another randomized clinical trial during this hospitalization
Pregnant or breast-feeding
Inability to comply with planned study procedures
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| Name | Affiliation | Role |
|---|---|---|
| Michael Felker, MD | Duke Clinical Research Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado at Denver and Health Sciences Center | Aurora | Colorado | 80045 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27654854 | Derived | Felker GM, Mentz RJ, Cole RT, Adams KF, Egnaczyk GF, Fiuzat M, Patel CB, Echols M, Khouri MG, Tauras JM, Gupta D, Monds P, Roberts R, O'Connor CM. Efficacy and Safety of Tolvaptan in Patients Hospitalized With Acute Heart Failure. J Am Coll Cardiol. 2017 Mar 21;69(11):1399-1406. doi: 10.1016/j.jacc.2016.09.004. Epub 2016 Sep 18. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Tolvaptan | IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours) |
| FG001 | Placebo |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Placebo | Drug | IV furosemide plus oral placebo (given at 0, 24 and 48 hours) |
|
| 0, 24, 48, and 72 hours |
| Fluid Loss | Change from baseline fluid balance at 24, 48, and 72 hours | 0, 24, 48, and 72 hours |
| Dyspnea Likert | Number of patients that experience moderate or greater improvement (patient reported) in dyspnea by 7 point Likert scale at 48 and 72 hours | 48 and 72 hours |
| Hospital Stay | Total days spent in hospital from baseline until discharge or death | 7 days |
| Worsening or Persistent Heart Failure or Death | Number of patients with worsening heart failure or death | 72 hrs |
| Over-diuresis | clinical evidence of volume depletion requiring intervention other than holding diuretics during the 72 hours after randomization | 72 hours |
| Serum Sodium | Change in serum sodium from baseline to 24, 48, and 72 hours | 0, 24, 48, and 72 hours |
| Dyspnea 11 Point NRS | Change in NRS for assessment of dyspnea from baseline to 24, 48, and 72 hours (scale ranges from 0-No difficulty breathing to 10-Difficulty as bad as you can imagine) | 0, 24, 48, and 72 hours |
| Freedom From Congestion | Jugular Venous Pressure (JVP) < 8 cm, no orthopnea, trace peripheral edema or less, and will be assessed at 24, 48, and 72 hours | 24, 48, and 72 hours |
| Development of Worsening Renal Function | increase in serum creatinine ≥ 0.3mg/dl from randomization at any time point during 72 hours after randomization | 72 hours |
| Days Hospitalized or Deceased | Total days hospitalized or deceased during the 30 days after randomization | 30 days |
| All Cause Death or Rehospitalization | All cause death or rehospitalization (to include unscheduled clinic visits or ED visits) at 30 days (Kaplan-Meier and 95% confidence interval) | 30 days |
| Emory University School of Medicine |
| Atlanta |
| Georgia |
| 30322 |
| United States |
| Northeast Georgia Heart Center | Gainesville | Georgia | 30501 | United States |
| Mercer University School of Medicine | Macon | Georgia | 31201 | United States |
| University of Chicago | Chicago | Illinois | 60637 | United States |
| Indiana University School of Medicine | Indianapolis | Indiana | 46202 | United States |
| Hennepin County Medical Center | Minneapolis | Minnesota | 55415 | United States |
| Montefiore Medical Center | The Bronx | New York | 10461 | United States |
| University of North Carolina at Chapel Hill | Chapel Hill | North Carolina | 27599 | United States |
| Novant Health Heart and Vascular | Charlotte | North Carolina | 28204 | United States |
| Duke University Medical Center | Durham | North Carolina | 27713 | United States |
| Southeastern Regional Medical Center | Lumberton | North Carolina | 28358 | United States |
| The Christ Hospital | Cincinnati | Ohio | 45219 | United States |
| University of Cincinnati Medical Center | Cincinnati | Ohio | 45267 | United States |
| Allegheny Valley Hospital | Natrona Heights | Pennsylvania | 15065 | United States |
| Grand View - Lehigh Valley Health Services | Sellersville | Pennsylvania | 18960 | United States |
| UT Southwestern Medical center | Dallas | Texas | 75390 | United States |
| Inova Heart and Vascular Institute | Falls Church | Virginia | 22042 | United States |
IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours) |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Tolvaptan | IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours) |
| BG001 | Placebo | IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours) |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours | The number of patients with at least moderate improvement (as reported by patient) in dyspnea Likert scale at both 8 AND 24 hours AND without the need for escalation of therapy due to worsening heart failure (rescue therapy) or death within 24 hours. | Baseline population | Posted | Count of Participants | Participants | 8 and 24 hours |
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| Secondary | Renal Function | Change in Serum creatinine from baseline to 24, 48 and 72 hours | Baseline population | Posted | Mean | Standard Deviation | mg/dL | 0, 24, 48 and 72 hours |
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| Secondary | Weight Loss | Change in body weight from baseline to 24, 48, and 72 hours | Baseline population | Posted | Mean | Standard Deviation | lbs | 0, 24, 48, and 72 hours |
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| Secondary | Fluid Loss | Change from baseline fluid balance at 24, 48, and 72 hours | baseline population | Posted | Mean | Standard Deviation | mL | 0, 24, 48, and 72 hours |
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| Secondary | Dyspnea Likert | Number of patients that experience moderate or greater improvement (patient reported) in dyspnea by 7 point Likert scale at 48 and 72 hours | baseline population | Posted | Count of Participants | Participants | 48 and 72 hours |
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| Secondary | Hospital Stay | Total days spent in hospital from baseline until discharge or death | baseline population | Posted | Mean | Standard Deviation | days | 7 days |
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| Secondary | Worsening or Persistent Heart Failure or Death | Number of patients with worsening heart failure or death | baseline population | Posted | Count of Participants | Participants | 72 hrs |
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| Secondary | Over-diuresis | clinical evidence of volume depletion requiring intervention other than holding diuretics during the 72 hours after randomization | baseline population | Posted | Count of Participants | Participants | 72 hours |
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| Secondary | Serum Sodium | Change in serum sodium from baseline to 24, 48, and 72 hours | baseline population | Posted | Mean | Standard Deviation | mmol/L | 0, 24, 48, and 72 hours |
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| Secondary | Dyspnea 11 Point NRS | Change in NRS for assessment of dyspnea from baseline to 24, 48, and 72 hours (scale ranges from 0-No difficulty breathing to 10-Difficulty as bad as you can imagine) | baseline population | Posted | Mean | Standard Deviation | units on a scale | 0, 24, 48, and 72 hours |
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| Secondary | Freedom From Congestion | Jugular Venous Pressure (JVP) < 8 cm, no orthopnea, trace peripheral edema or less, and will be assessed at 24, 48, and 72 hours | baseline population | Posted | Count of Participants | Participants | 24, 48, and 72 hours |
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| Secondary | Development of Worsening Renal Function | increase in serum creatinine ≥ 0.3mg/dl from randomization at any time point during 72 hours after randomization | baseline population | Posted | Count of Participants | Participants | 72 hours |
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| Secondary | Days Hospitalized or Deceased | Total days hospitalized or deceased during the 30 days after randomization | baseline population | Posted | Mean | Standard Deviation | days | 30 days |
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| Secondary | All Cause Death or Rehospitalization | All cause death or rehospitalization (to include unscheduled clinic visits or ED visits) at 30 days (Kaplan-Meier and 95% confidence interval) | baseline population | Posted | Mean | 95% Confidence Interval | proportion of participants | 30 days |
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Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tolvaptan | IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours) | 8 | 129 | 101 | 129 | ||
| EG001 | Placebo | IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours) | 2 | 128 | 107 | 128 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Blood Sodium Increase | Renal and urinary disorders | MedDRA 19.0 | Systematic Assessment |
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| Epistaxis | Blood and lymphatic system disorders | MedDRA 19.0 | Systematic Assessment |
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| Cerebrovascular Accident | Vascular disorders | MedDRA 19.0 | Systematic Assessment |
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| Hypotension | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Cardiogenic Shock | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Uterine Cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 19.0 | Systematic Assessment |
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| Chronic Obstructive Pulmonary Disease | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Sepsis | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
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| Hyponatraemia | Renal and urinary disorders | MedDRA 19.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial Fibrillation | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Ventricular Tachycardia | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Myocardial Infarction | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Acute Coronary Syndrome | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Acute Renal Failure | Renal and urinary disorders | MedDRA 19.0 | Systematic Assessment |
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| Worsening Heart Failure | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Death | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| G. Michael Felker, MD | Duke Clinical Research Institute | 919-668-8919 | Michael.Felker@duke.edu |
| ID | Term |
|---|---|
| D006333 | Heart Failure |
| D004417 | Dyspnea |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000077602 | Tolvaptan |
| ID | Term |
|---|---|
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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