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

NCT01314066 | Withdrawn Phase 2 DMC

• 1 other identifier: IRB Protocol #0907010498
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Severe Sepsis; Acute Respiratory Distress Syndrome

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• 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

Study Arms (3)

Bevacizumab 5 mg/kg

EXPERIMENTAL

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

Drug: Bevacizumab

Bevacizumab at 10 mg/kg

EXPERIMENTAL

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

Drug: Bevacizumab

Placebo

PLACEBO COMPARATOR

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

Interventions

Bevacizumab 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.

Also known as: Avastin

Bevacizumab 5 mg/kg; Bevacizumab at 10 mg/kg

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical Diagnosis of Sepsis based on Modified Inflammatory Response Syndrome (SIRS) Criteria
• Evidence of a systemic response to infection
• or more sepsis-induced organ failures modified from those as defined by Bernard, et al. (eg. PROWESS rhAPC study, NEJM)

You may not qualify if:

• 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)

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead

Study Sites (1)

Weill Cornell Medical College-New York Presbyterian Hospital

New York, New York, 10065, United States

Location

Related Publications (18)

• 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.

  PMID: 10793167 BACKGROUND

• 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.

  PMID: 19011152 BACKGROUND

• 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.

  PMID: 10837361 BACKGROUND

• 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.

  PMID: 16236739 BACKGROUND

• 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.

  PMID: 16714767 BACKGROUND

• 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.

  PMID: 11471568 BACKGROUND

• 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.

  PMID: 15671629 BACKGROUND

• 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.

  PMID: 19176759 BACKGROUND

• 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.

  PMID: 16702604 BACKGROUND

• 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.

  PMID: 15614129 BACKGROUND

• 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.

  PMID: 17568329 BACKGROUND

• 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.

  PMID: 19254174 BACKGROUND

• 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.

  PMID: 7091520 BACKGROUND

• 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.

  PMID: 7509706 BACKGROUND

• 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.

  PMID: 16134000 BACKGROUND

• 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.

  PMID: 18520292 BACKGROUND

• 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.

  PMID: 18324912 BACKGROUND

• 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.

  PMID: 18598002 BACKGROUND

MeSH Terms

Conditions

Sepsis; Respiratory Distress Syndrome

Interventions

Bevacizumab

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Robert Kaner, MD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 28, 2010
• First Posted: March 14, 2011
• Study Start: July 1, 2010
• Primary Completion: November 1, 2015
• Study Completion: February 1, 2016
• Last Updated: May 3, 2016

Record last verified: 2016-04

Locations

US (1)