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

NCT ID: NCT01314066

Last Updated: 2016-05-03

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

WITHDRAWN

Clinical Phase

PHASE2

Study Classification

INTERVENTIONAL

Study Start Date

2010-07-31

Study Completion Date

2016-02-29

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.

Conditions

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Severe Sepsis Acute Respiratory Distress Syndrome

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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Bevacizumab 5 mg/kg

Receive drug solution as a single dose. Treatment will be given as 90 minute IV infusion.

Group Type EXPERIMENTAL

Bevacizumab

Intervention Type DRUG

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.

Bevacizumab at 10 mg/kg

Receive drug solution as a single dose. Treatment will be given as 90 minute IV infusion.

Group Type EXPERIMENTAL

Bevacizumab

Intervention Type DRUG

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.

Placebo

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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Patients assigned to placebo-control group will receive a single dose of saline solution as a 90 minute IV infusion

Interventions

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Bevacizumab

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.

Intervention Type DRUG

Placebo

Patients assigned to placebo-control group will receive a single dose of saline solution as a 90 minute IV infusion

Intervention Type DRUG

Other Intervention Names

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Avastin

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
Minimum Eligible Age

18 Years

Maximum Eligible Age

99 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Weill Medical College of Cornell University

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Robert Kaner, MD

Role: PRINCIPAL_INVESTIGATOR

Weill Medical College of Cornell University

Locations

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Weill Cornell Medical College-New York Presbyterian Hospital

New York, New York, United States

Site Status

Countries

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United States

References

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Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1334-49. doi: 10.1056/NEJM200005043421806. No abstract available.

Reference Type BACKGROUND
PMID: 10793167 (View on PubMed)

Phua J, Badia JR, Adhikari NK, Friedrich JO, Fowler RA, Singh JM, Scales DC, Stather DR, Li A, Jones A, Gattas DJ, Hallett D, Tomlinson G, Stewart TE, Ferguson ND. Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review. Am J Respir Crit Care Med. 2009 Feb 1;179(3):220-7. doi: 10.1164/rccm.200805-722OC. Epub 2008 Nov 14.

Reference Type BACKGROUND
PMID: 19011152 (View on PubMed)

Kaner RJ, Ladetto JV, Singh R, Fukuda N, Matthay MA, Crystal RG. Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema. Am J Respir Cell Mol Biol. 2000 Jun;22(6):657-64. doi: 10.1165/ajrcmb.22.6.3779.

Reference Type BACKGROUND
PMID: 10837361 (View on PubMed)

Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med. 2005 Oct 20;353(16):1685-93. doi: 10.1056/NEJMoa050333.

Reference Type BACKGROUND
PMID: 16236739 (View on PubMed)

National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564-75. doi: 10.1056/NEJMoa062200. Epub 2006 May 21.

Reference Type BACKGROUND
PMID: 16714767 (View on PubMed)

Kaner RJ, Crystal RG. Compartmentalization of vascular endothelial growth factor to the epithelial surface of the human lung. Mol Med. 2001 Apr;7(4):240-6.

Reference Type BACKGROUND
PMID: 11471568 (View on PubMed)

Kaner RJ, Crystal RG. Pathogenesis of high altitude pulmonary edema: does alveolar epithelial lining fluid vascular endothelial growth factor exacerbate capillary leak? High Alt Med Biol. 2004 Winter;5(4):399-409. doi: 10.1089/ham.2004.5.399.

Reference Type BACKGROUND
PMID: 15671629 (View on PubMed)

Hao Q, Wang L, Tang H. Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells. Am J Physiol Cell Physiol. 2009 Apr;296(4):C821-7. doi: 10.1152/ajpcell.00504.2008. Epub 2009 Jan 28.

Reference Type BACKGROUND
PMID: 19176759 (View on PubMed)

Yano K, Liaw PC, Mullington JM, Shih SC, Okada H, Bodyak N, Kang PM, Toltl L, Belikoff B, Buras J, Simms BT, Mizgerd JP, Carmeliet P, Karumanchi SA, Aird WC. Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med. 2006 Jun 12;203(6):1447-58. doi: 10.1084/jem.20060375. Epub 2006 May 15.

Reference Type BACKGROUND
PMID: 16702604 (View on PubMed)

van der Flier M, van Leeuwen HJ, van Kessel KP, Kimpen JL, Hoepelman AI, Geelen SP. Plasma vascular endothelial growth factor in severe sepsis. Shock. 2005 Jan;23(1):35-8. doi: 10.1097/01.shk.0000150728.91155.41.

Reference Type BACKGROUND
PMID: 15614129 (View on PubMed)

Tsao PN, Chan FT, Wei SC, Hsieh WS, Chou HC, Su YN, Chen CY, Hsu WM, Hsieh FJ, Hsu SM. Soluble vascular endothelial growth factor receptor-1 protects mice in sepsis. Crit Care Med. 2007 Aug;35(8):1955-60. doi: 10.1097/01.CCM.0000275273.56547.B8.

Reference Type BACKGROUND
PMID: 17568329 (View on PubMed)

Watanabe M, Boyer JL, Crystal RG. Genetic delivery of bevacizumab to suppress vascular endothelial growth factor-induced high-permeability pulmonary edema. Hum Gene Ther. 2009 Jun;20(6):598-610. doi: 10.1089/hum.2008.169.

Reference Type BACKGROUND
PMID: 19254174 (View on PubMed)

Pepe PE, Potkin RT, Reus DH, Hudson LD, Carrico CJ. Clinical predictors of the adult respiratory distress syndrome. Am J Surg. 1982 Jul;144(1):124-30. doi: 10.1016/0002-9610(82)90612-2.

Reference Type BACKGROUND
PMID: 7091520 (View on PubMed)

Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):818-24. doi: 10.1164/ajrccm.149.3.7509706.

Reference Type BACKGROUND
PMID: 7509706 (View on PubMed)

Nolan A, Weiden MD, Thurston G, Gold JA. Vascular endothelial growth factor blockade reduces plasma cytokines in a murine model of polymicrobial sepsis. Inflammation. 2004 Oct;28(5):271-8. doi: 10.1007/s10753-004-6050-3.

Reference Type BACKGROUND
PMID: 16134000 (View on PubMed)

Wakelee H. Antibodies to vascular endothelial growth factor in non-small cell lung cancer. J Thorac Oncol. 2008 Jun;3(6 Suppl 2):S113-8. doi: 10.1097/JTO.0b013e318174e993.

Reference Type BACKGROUND
PMID: 18520292 (View on PubMed)

Watanabe M, Boyer JL, Hackett NR, Qiu J, Crystal RG. Genetic delivery of the murine equivalent of bevacizumab (avastin), an anti-vascular endothelial growth factor monoclonal antibody, to suppress growth of human tumors in immunodeficient mice. Hum Gene Ther. 2008 Mar;19(3):300-10. doi: 10.1089/hum.2007.109.

Reference Type BACKGROUND
PMID: 18324912 (View on PubMed)

Shapiro NI, Yano K, Okada H, Fischer C, Howell M, Spokes KC, Ngo L, Angus DC, Aird WC. A prospective, observational study of soluble FLT-1 and vascular endothelial growth factor in sepsis. Shock. 2008 Apr;29(4):452-7. doi: 10.1097/shk.0b013e31815072c1.

Reference Type BACKGROUND
PMID: 18598002 (View on PubMed)

Other Identifiers

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IRB Protocol #0907010498

Identifier Type: -

Identifier Source: org_study_id

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