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

Acute Respiratory Distress Syndrome Clinical Trial

— VEGF-ARDS  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01314066
• Other study ID #: IRB Protocol #0907010498
• Status: Withdrawn
• Phase: Phase 2
• First received: July 28, 2010
• Last updated: April 29, 2016
• Start date: July 2010
• Est. completion date: February 2016

Study information

• Verified date: April 2016
• Source: Weill Medical College of Cornell University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: February 2016
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 99 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn
• Severe Sepsis
• Syndrome

Intervention

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

Locations

Country	Name	City	State
United States	Weill Cornell Medical College-New York Presbyterian Hospital	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Weill Medical College of Cornell University

Country where clinical trial is conducted

United States, 

References & Publications (18)

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. Epub 2006 May 21. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1334-49. Review. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2006 May 15. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of individuals progressing to meet RDS criteria as defined by the American- European ARDS consensus conference and as used by ARDSnet.		Day 28	No
Secondary	Ventilator-free days to Day 28		Day 28	No
Secondary	28 day all-cause mortality		Day 28	No
Secondary	Proportion of subjects progressing to acute lung injury (who do not meet the definition at randomization)		Day 28	No
Secondary	Worst PaO2/FiO2 ratio recorded following enrollment		Day 3 and 28	No
Secondary	Change in PaO2/FiO2 ratio between Day 0 to Day 3		Day 0 and Day 3	No
Secondary	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	No
Secondary	Proportion of subjects surviving to hospital discharge		Hospital Discharge Day	No
Secondary	Vasopressor-free days		Day 28	No
Secondary	Reversal of shock if present at randomization.		Day 28	No