Efficacy of Bevacizumab in Preventing Acute Respiratory Distress Syndrome (ARDS)

Study Overview
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Brief Summary
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This study aims to test the effectiveness of a single intravenous (IV, through the vein) dose of the study drug, bevacizumab (Avastin), in preventing/reducing the development of Acute Respiratory Distress Syndrome (ARDS), in patients with severe sepsis, who are at high risk for developing ARDS. ARDS is a lung disease caused by a lung injury that leads to lung function impairment. The condition the patient has,severe sepsis, is a medical condition associated with an infection characterized as an immune system inflammatory response throughout your whole body that can lead to organ dysfunction, low blood pressure or insufficient blood flow to one or more of your organs.

Detailed Description
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Acute respiratory distress syndrome (ARDS) is the most extreme form of acute lung injury (ALI) that results in a loss of lung function and structure. Vascular endothelial growth factor (VEGF), a protein critical for lung development that is found in the thin layer of liquid lining the inner surface of the lung air sacs, is believed to play a key role in the development of ARDS. During ARDS/ALI, VEGF markedly increases the permeability of the cells lining the inner surface of blood vessels in the lungs, which leads to an accumulation of fluid in the lungs (pulmonary edema), a characteristic of ARDS/ALI. Thus, anti-VEGF therapies offer a unique approach to treat this potentially fatal disorder. Bevacizumab (Avastin ®), an anti-VEGF medication, has been shown to be effective in inhibiting pulmonary edema caused by VEGF over-expression in an animal model. This study will establish the usefulness and effectiveness of a singe dose of Bevacizumab administered intravenously (through the vein) in reducing the incidence of ARDS in individuals with severe sepsis (a condition characterized by an inflammatory response by the immune system throughout the whole body caused by infection) who are at high risk for the development of ARDS. All study participants will be randomized to receive placebo, bevacizumab 5 mg/kg or bevacizumab 10 mg/kg as a single intravenous dose in a double-blinded fashion in addition to traditional sepsis treatment.

Official Title
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Efficacy of Bevacizumab in Preventing Acute Respiratory Distress Syndrome (ARDS)

Conditions
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Severe Sepsis, Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical Diagnosis of Sepsis based on Modified Inflammatory Response Syndrome (SIRS) Criteria Evidence of a systemic response to infection 1 or more sepsis-induced organ failures modified from those as defined by Bernard, et al. (eg. PROWESS rhAPC study, NEJM) Exclusion Criteria: Pregnant females Systolic blood pressure >170 Diastolic blood pressure >110 Preexisting proteinuria >0.3 g/24hr Known hypersensitivity to bevacizumab Subject or health care agent unable to provide written informed consent Diagnosis of lung cancer with active hemoptysis Patient not expected to survive 28 days independently of the septic episode due to severe underlying disease Presence of an advanced directive to withhold life-sustaining treatment Participation in another investigational study within 30 days of enrollment GI tract perforation and/or repair unless surgical incision is fully healed Any major surgery in the 28 days prior to enrollment Need for non-elective major surgery within 28 days Presence of enterocutaneous fistula (an abnormal connection between body cavities, in this case, from the intestine to the skin. Possible complication of surgery, where passageway progresses from intestine to surgery site to skin) Known or suspected tracheoesophageal fistula (an abnormal connection between the esophagus and the trachea) Current ICU stay of > 2 months prior to enrollment Need for therapeutic anti-coagulation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab 5 mg/kg<br>Receive drug solution as a single dose. Treatment will be given as 90 minute IV infusion. | Drug: Bevacizumab<br>* Patients receiving drug will receive it as a single dose. Treatment will be given as 90-minute IV infusion. The patient will either receive Bevacizumab at 5 mg/kg OR Bevacizumab at 10 mg/kg.<br>* Other names: Avastin;|
| Experimental: Bevacizumab at 10 mg/kg<br>Receive drug solution as a single dose. Treatment will be given as 90 minute IV infusion. | Drug: Bevacizumab<br>* Patients receiving drug will receive it as a single dose. Treatment will be given as 90-minute IV infusion. The patient will either receive Bevacizumab at 5 mg/kg OR Bevacizumab at 10 mg/kg.<br>* Other names: Avastin;|
| Placebo Comparator: Placebo<br>In addition to receiving the best standard supportive care for both diagnosis and treatment for individuals diagnosed with severe sepsis, they will receive an IV saline solution. | Drug: Placebo<br>* Patients assigned to placebo-control group will receive a single dose of saline solution as a 90 minute IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of individuals progressing to meet RDS criteria as defined by the American- European ARDS consensus conference and as used by ARDSnet. |  | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-free days to Day 28 |  | Day 28 | 
| 28 day all-cause mortality |  | Day 28 | 
| Proportion of subjects progressing to acute lung injury (who do not meet the definition at randomization) |  | Day 28 | 
| Worst PaO2/FiO2 ratio recorded following enrollment |  | Day 3 and 28 | 
| Change in PaO2/FiO2 ratio between Day 0 to Day 3 |  | Day 0 and Day 3 | 
| Change from baseline in number of non-lung organ failures using the Multi-Organ Dysfunction (MOD) score and Sepsis Organ Failure Assessment (SOFA) score |  | Day 0, Day 28 | 
| Proportion of subjects surviving to hospital discharge |  | Hospital Discharge Day | 
| Vasopressor-free days |  | Day 28 | 
| Reversal of shock if present at randomization. |  | Day 28 |