Comparative Evaluation of Albumin and Starch Effects in Acute Lung Injury (ALI)

Study Overview
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Brief Summary
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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are similar conditions in which the lungs are critically injured by another inflammatory process in the body. Together they affect more than 150,000 people per year in the United States, with mortality approaching 50% and a financial burden estimated to exceed $5 billion. Fluid overload, weight gain, and reduced oncotic pressure (low blood proteins) are associated with prolonged need for mechanical ventilation and mortality in patients with ALI/ARDS. Historical studies have provided conflicting evidence for benefits with colloid or diuretic therapy in ALI/ARDS, but recent clinical trials have demonstrated significant improvements in blood oxygen levels. The mechanisms of these benefits are not yet certain, but appear to relate to albumin's (a protein medicine) specific ability to influence injury and inflammation in the lungs, thus improving the ability for the lung to repair and exchange oxygen. The purpose of this project is to determine the effects of therapies that affect blood proteins on their ability to change the way the lungs and cardiovascular system (heart and blood vessels) function. Special measurements will be taken to understand how these protein medicines change the ability of the lung and whole body to recover from widespread injury, with additional measures of specific heart and lung function. This clinical trial randomizes ALI/ARDS patients with low blood protein levels to receive albumin (a natural blood protein that is known to influence inflammation) or hetastarch (a synthetic blood protein) with diuretic therapy targeted to improve respiratory function. Therapeutic effects on respiratory function and blood oxygen levels, extravascular lung water, oncotic pressure, lung fluid removal, and heart function will be characterized. This trial will advance our understanding of treatment of ALI/ARDS and the factors that affect fluid balance in the lungs of these patients. Funding Source - FDA Office of Orphan Products Development (OOPD)

Official Title
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Phase III Study Comparing Albumin and Hetastarch Therapy in Acute Lung Injury

Conditions
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Lung Injury, Acute (ALI), Respiratory Distress Syndrome, Acute (ARDS)

Intervention / Treatment
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* Drug: 5% human albumin
* Drug: 6% hetastarch


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consensus clinical definition of ALI or ARDS: Partial pressure of oxygen in arterial blood to the fraction of inspired oxygen (PaO2 / FiO2) ratio ≤ 200 (ARDS) or ≤ 300 (ALI), and; Bilateral infiltrates on chest x-ray, and; No clinical evidence of congestive heart failure, and; Pulmonary artery occlusion pressure (PAOP) ≤ 18 mm Hg, if a pulmonary arterial catheter is present Serum total protein concentration < 6.0 g/dL. Endotracheal intubation and mechanical ventilation ≥ 24 hours. Exclusion Criteria: Hemodynamic instability within the prior 24 hours: (either of the following) Ongoing fluid resuscitation defined as > 2 liters of crystalloid boluses or > 4 units of blood products transfused in the prior 24-hour period. Vasopressor support exceeding any of the following: Dopamine or dobutamine > 5 mcg/kg/min, or in combination at any dose; or Any other vasoactive agent (i.e. epinephrine, norepinephrine, phenylephrine) Significant renal disease (either of the following at the time of screening): End-stage renal disease, or Renal insufficiency with serum creatinine ≥ 3.0 mg/dL or urine output < 500cc/24 hrs Allergy to albumin, hetastarch or furosemide. Increased risk for bleeding: Within 72 hours of any surgical procedure requiring use of the operating room, or Any current or previously diagnosed bleeding disorder, or History of any intracranial abnormality (including, but not limited to, intracranial arteriovenous malformations, subdural/subarachnoid/intracerebral hemorrhage, intracranial mass lesions) or traumatic brain injury with Glasgow Coma Scal (GCS) < 9 in the prior 14 days, or Prothrombin time international normalized ratio (INR) > 2.0, partial thromboplastin time (PTT) > 1.5 times control, platelet count < 50,000/cc3 Risk for worsening pulmonary edema due to systolic heart failure. Technical pulse contour analysis limitations: Absence of central venous catheter, clinical arterial vascular disease, severe hypothermia (core temperature < 94°F), weight < 40 kg or > 250 kg, clinically significant bleeding diathesis. Failure of the patient or nearest relative to provide informed consent. Refusal of the patient's attending physician to provide consent to participate. Age < 18 years. Pregnancy. Inability to quantify urine output (e.g. absence of bladder or bladder catheter). Significant hypokalemia (K+ < 3.5 meq/L), hypernatremia (Na+ > 155 meq/L) or hypomagnesemia (Mg < 1.0 meq/L) Patient meets criteria for weaning mechanical ventilation: Required FiO2 ≤ 0.40 and positive end-expiratory pressure (PEEP) ≤ 5, and; Spontaneous tidal volumes > 5 ml / kg, and; Spontaneous respiratory rate < 20 / minute, and; Capable of spontaneous ventilation on continuous positive airway pressure (CPAP)=5, pressure support (PS)=5. Expected survival ≤ 120 hours.

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>Intravenous 5% human albumin | Drug: 5% human albumin<br>* Intravenous administration of 250 milliliters (mL) 5% human albumin every 8 hours for 5 days<br>|
| Experimental: 2<br>Intravenous 6% hetastarch | Drug: 6% hetastarch<br>* Intravenous administration of 250mL 6% hetastarch every 8 hours for 5 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Extravascular Lung Water (EVLW) | Quantity of extravascular lung water (EVLW) measured by transpulmonary thermodilution. Higher measurements of EVLW per kilogram of body weight indicate increased lung injury. Normal values for EVLW are thought to be less than 10 mL/kg. | Baseline to Day 5 (120 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Oxygenation (PaO2/FiO2 Ratio) | Change in arterial oxygenation measured by arterial blood gas analysis. The partial pressure of O2 in arterial blood to fraction of inspired oxygen ratio (PaO2/FiO2) is a ratio of partial pressure arterial oxygen to fractional inspired inspired oxygen. This ratio is used as an indicator of hypoxemia (low blood oxygen). A PaO2/FiO2 ratio of 200-300 indicates mild ARDS, 100-200 indicates moderate ARDS, and less than 100 indicates severe ARDS. | Baseline, Day 1 | 
| Ventilator-free Days | The 'ventilator free survival days' in a 30-day period is a previously validated method of comparing groups with respect to mechanical ventilator requirements while adjusting for mortality. This variable represents the number of days in the 30-day period following baseline that the patient is alive and not requiring mechanical ventilation. | Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute lung injury (ALI), Acute respiratory distress syndrome (ARDS), Respiratory failure