Tezosentan in Acute Heart Failure

Study Overview
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Brief Summary
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The randomized patients with acute heart failure will be stratified based on the presence or absence of a Swan-Ganz catheter and assigned to receive either tezosentan 5 mg/h for the first 30 minutes and 1 mg/h thereafter or matching placebo in a 1:1 manner. The duration of the treatment is 24 hours up to 72 hours. The duration of the follow-up period is 30 days after treatment initiation for death, re-hospitalizations and SAEs followed by a follow-up period of 5 months for vital status.

Official Title
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Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Study to Assess the Efficacy, Safety, and Tolerability of Tezosentan in Patients With Acute Heart Failure.

Conditions
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Acute Heart Failure, Acute Decompensation of Chronic Heart Failure, New Onset of Heart Failure

Intervention / Treatment
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* Drug: tezosentan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 years of age or older. Male or non-breast-feeding, non-pregnant female (only females who are post menopausal, surgically sterile or practicing a reliable method of contraception). Acute heart failure (ischemic or non-ischemic). Randomization within 24 hours of hospitalization (including emergency room stay) for acute heart failure. Dyspnea at rest as assessed by the patient and breathing rate ³ 24/min (measured during 60 seconds). At least two out of the following four criteria: · elevated BNP or N terminal pro-BNP (more than three times the upper limit of normal for the site) in patients not treated with nesiritide,· clinical evidence of pulmonary congestion/edema (e.g., rales or crackles more than a third above bases),· evidence of pulmonary congestion on chest X-ray, · left ventricular systolic dysfunction (EF < 40% or wall motion index £ 1.2 within 12 months prior to randomization). Patients in need of i.v. therapy for acute heart failure and who have received at least one dose of i.v. diuretic within 24 hours prior to study drug initiation (last bolus dose must have been more than 2 hours prior to study drug initiation). Written informed consent. Exclusion Criteria: Criteria only for patients hemodynamically monitored: Baseline cardiac index > 2.5 l/min/m2 and/or PCWP < 20 mmHg within 6 hours prior to study drug initiation. Criteria for all patients: Patients not receiving i.v. vasodilators (e.g., nitrates, nitroprusside, nesiritide) at baseline: supine systolic blood pressure < 100 mmHg. Patients receiving i.v. vasodilators (e.g., nitrates, nitroprusside, nesiritide) at baseline: supine systolic blood pressure < 120 mmHg. Cardiogenic shock within the last 48 hours or evidence of volume depletion. Ongoing myocardial ischaemia, coronary revascularisation procedure (PCI or CABG) during current admission or planned revascularisation. ST-segment elevation myocardial infarction or administration of thrombolytic therapy. Baseline creatinine ≥ 2.5 mg/dl (221 mmol/l). Baseline hemoglobin < 10 g/dl or a hematocrit < 30%. Hemodialysis, ultrafiltration or peritoneal dialysis within the last 7 days. Heart failure due to active myocarditis, obstructive hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy or constrictive pericarditis. Heart failure caused by valvular disease. Acute heart failure associated with uncontrolled hemodynamically relevant atrial fibrillation/flutter or ventricular rhythm disturbances. Acute heart failure secondary to clinical evidence of digoxin toxicity or any other drug-related toxicity. Significant chronic and/or acute lung disease that might interfere with the ability to interpret the dyspnea assessments or hemodynamic measurements (e.g., severe chronic obstructive pulmonary disease or acute pneumonia). Mechanical circulatory or ventilatory support. Prior CPAP use is allowed, if discontinued at least 2 hours prior to study drug initiation. Acute systemic infection/sepsis or other illness with a life expectancy less than 30 days. Coronary artery bypass graft, or other cardiac surgery, or major non-cardiac surgery within the last 30 days. Patients who received another investigational drug within 30 days prior to randomization. Re-randomization in the current study. Any factors that might interfere with the study conduct or interpretation of the results such as known drug or alcohol dependence. Concomitant treatment with cyclosporin A or tacrolimus.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>tezosentan delivered i.v. at 20 mL/h (5 mg/h) for 30 min followed by 4ML/h (1 mg/h) for 23.5 to 71.5 h (24 to 72 h in total) | Drug: tezosentan<br>* tezosentan delivered i.v. at 20 mL/h (5 mg/h) for 30 min followed by 4ML/h (1 mg/h) for 23.5 to 71.5 h (24 to 72 h in total)<br>|
| Placebo Comparator: 2<br> | Drug: tezosentan<br>* tezosentan delivered i.v. at 20 mL/h (5 mg/h) for 30 min followed by 4ML/h (1 mg/h) for 23.5 to 71.5 h (24 to 72 h in total)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of death or worsening heart failure |  | 7 days following study drug initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| effect on patient's dyspnea assessment, measured using a visual analog scale |  | Over first 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute heart failure, Actelion, tezosentan, acute decompensation of chronic heart failure, New onset of heart failure