Safety and Efficacy of Conivaptan in Hyponatremic Patients With Symptomatic Acute Decompensated Heart Failure (ADHF)

Study Overview
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Brief Summary
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This study will evaluate the safety and effectiveness of Conivaptan, a vasopressin antagonist, in the treatment of hyponatremic subjects having symptomatic acute decompensated heart failure (ADHF).

Detailed Description
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Subjects will be recruited from the Emergency Department. It is expected that subjects will be treated according to the institution's accepted conventional therapy protocol for the treatment of ADHF. Therapy may also include the use of loop diuretics for the relief of pulmonary congestion and maintenance of adequate urine output.

Official Title
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A Phase-3b, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Safety and Efficacy of Conivaptan in Symptomatic Acute Decompensated Heart Failure (ADHF) Subjects With Hyponatremia

Conditions
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Hyponatremia, Acute Decompensated Heart Failure

Intervention / Treatment
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* Drug: conivaptan
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presents to emergency department with documented history of CHF and symptomatic ADHF, will be treated for ADHF, and primary reason for admission to the hospital is ADHF Dyspnea at rest or with minimal exertion and must have moderate shortness of breath (SOB) in any of the first three Provocative Dyspnea Assessment positions Severe pulmonary congestion as evidenced by jugular venous distention or lower extremity/sacral edema or rales upon chest auscultation or chest x-ray. BNP > 400 or NT-pro BNP > 1500 drawn during Screening Systolic blood pressure >= 100 mmHg to < 180 mmHg at time of start of study drug Serum sodium value >= 115 mEq/L (115 mmol/L) and < 135 mEq/L (135 mmol/L) during Screening Exclusion Criteria: Clinical evidence of volume depletion Active ongoing acute coronary syndrome or acute ST segment elevation myocardial infarction (or has experienced a myocardial infarction within 30 days of Screening) In cardiogenic shock Calculated creatinine clearance < 30 mL/min/1.73 m2 as estimated by the Modification of Diet in Renal Disease (MDRD) equation, has received intravenous (IV) contrast agent within 72 hours prior to randomization or is expected to receive IV contrast agent within the first 72 hours of study participation Ultrafiltration within the past 72 hours. Currently using or expected to use inotropic therapy Cardiac bypass grafts in the past 60 days Cerebrovascular accident in the past 30 days Uncontrolled brady- or ventricular tachyarrhythmias requiring emergent pacemaker placement or treatment Hemodynamically significant uncorrected primary cardiac valvular disease or hypertrophic cardiomyopathy Untreated severe hypothyroidism, hyperthyroidism or adrenal insufficiency based on medical history ALT or AST elevations > 5 times upper limit of normal Biliary liver cirrhosis, history or presence of severe hepatic encephalopathy, ascites, esophageal variceal bleeding within the past three months, severe portal hypertension or surgical portosystemic shunt. Received any organ transplant, clinical diagnosis of pneumonia, symptomatic hyponatremia requiring urgent intervention or any concurrent illness which, in the opinion of the investigator, may interfere with treatment or evaluation of safety Pregnant or lactating Currently using vasopressin, oxytocin or desmopressin

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching loading dose and continuous intravenous infusion for 48 hours | Drug: placebo<br>* Premix bag<br>|
| Experimental: Conivaptan<br>20mg loading dose followed by a 20mg/ day continuous intravenous infusion for 48 hours | Drug: conivaptan<br>* Premix bag<br>* Other names: Vaprisol; YM087;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Renal Function From Baseline at 72 Hours Assessed by Calculated Creatinine Clearance (MDRD Equation) | MDRD = Modification of Diet in Renal Disease The MDRD equation is a standard calculation for estimated glomerular filtration rate. Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | Baseline and 72 Hours | 
| Assessment of Dyspnea at 24 Hours as Determined by a 7-point Likert Scale | Dyspnea is defined as the sensation of uncomfortable or difficult breathing. Changes in Dyspnea were assessed using the following 7-point scale: 1-Markedly worse; 2-Moderately worse; 3-Mildly worse; 4-No change; 5-Mildly improved; 6-Moderately improved; 7-Markedly better/improved. Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | 24 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Renal Function From Baseline at Hours 24, 48 and 72 as Assessed by Urine Creatinine Clearance | Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | Baseline, 24 Hours, 48 Hours and 72 Hours | 
| Change in Renal Function From Baseline at Hours 24, 48 and Day 9 (or Day of Discharge) as Assessed by Serum Creatinine Concentration and Calculated Creatinine Clearance | Calculated creatinine clearance is only calculated through hour 72 using the MDRD equation. MDRD = Modification of Diet in Renal Disease The MDRD equation is a standard calculation for estimated glomerular filtration rate. Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | Baseline, 24 Hours, 48 Hours and Day 9 | 
| Incidence of Use of Rescue Therapy or Other Intervention (Including Dialysis) Because of Worsening Renal Function | Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | Day 9 | 
| Termination of Study Drug Due to an Adverse Event or Intolerability | Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | 48.5 Hours | 
| Assessment of Dyspnea at Baseline, Hours 6, 12, 24 and 48 Using a Relative Dyspnea Assessment | Dyspnea is defined as the sensation of uncomfortable or difficult breathing. Changes in Dyspnea were assessed using the following 7-point Likert scale: 1-Markedly worse; 2-Moderately worse; 3-Mildly worse; 4-No change; 5-Mildly improved; 6-Moderately improved; 7-Markedly better/improved. Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | Baseline, 6 Hours, 12 Hours, 24 Hours and 48 Hours | 
| Assessment of Dyspnea at Baseline, Hours 6, 12, 24 and 48 Using a Provocative Dyspnea Assessment | Dyspnea is defined as the sensation of uncomfortable or difficult breathing. The Provocative Dyspnea Assessment assesses dyspnea and changes in dyspnea from Baseline on a 5-point Likert scale at 5 different positions and assigns a Dyspnea Severity Score that ranges from 1 (worst severity) to 25 (least severity). Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | Baseline, 6 Hours, 12 Hours, 24 Hours and 48 Hours | 
| Change From Baseline in Body Weight at Hours 24, 48 and 72 and Days 6 and 9 (or Day of Discharge) | Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | Baseline, 24 Hours, 48 Hours, 72 Hours, Day 6 and Day 9 | 
| Total Loop Diuretic Use Through 48 Hours | Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | 48 Hours | 
| Total Urine Output at Hours 6, 12, 24, 48 and 72 | Outcome Measures were not analyzed due to the abbreviated enrollment at early study termination. | 6 Hours, 12 Hours, 24 Hours, 48 Hours and 72 Hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyponatremia, euvolemic hyponatremia, hypervolemic hyponatremia, acute decompensated heart failure, conivaptan, Vaprisol