Pilot Study of Bevacizumab (Avastin) in Patients With Septic Shock

The purpose of this study is to perform a pilot study to assess the potential use of Bevacizumab (a vascular endothelial growth factor (VEGF) inhibitor) in sepsis.

Study Overview

• Status: Withdrawn
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Placebo; Drug: Bevacizumab

Detailed Description

Sepsis is responsible for significant morbidity, mortality, and costs to patients in our healthcare system. The hospital case mortality rate for severe sepsis (sepsis with acute organ system dysfunction) is between 30-50%,7-12 with an incidence of approximately 751,000 cases and 215,000 deaths nationally per year. The overall cost of care is estimated at $16.7 billion annually in the US.Despite significant advances in medical science, the overall mortality rate for severe sepsis has not improved substantially over time.

VEGF signaling and sepsis. VEGF contributes to inflammation and coagulation - the key elements in sepsis pathophysiology. For example, under in vitro conditions, VEGF induces the expression of cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1) in endothelial cells and promotes adhesion of leukocytes. Moreover, VEGF signaling upregulates tissue factor mRNA, protein and procoagulant activity. Several studies have shown increased circulating levels of VEGF in patients with sepsis. In one study, maximum VEGF levels were increased in survivors versus non-survivors in sepsis. In another study of patients with meningococcal meningitis, elevated VEGF levels were associated with shock and upregulation of IL-1beta, IL-10, IL-12, complement activation and increased permeability.We have additional human data on 83 patients demonstrating an association of VEGF with SOFA score, IL-1, and IL-6. Consistent with its critical role in inflammation, VEGF inhibition using a VEGF trap resulted in attenuation of plasma interleukin IL-6 and IL-10 levels in a mouse cecal ligation puncture (CLP) model.

VEGF signaling is an important determinant of sepsis morbidity and mortality in animal models. We have recently shown that sepsis is associated with a time-dependent increase in circulating levels of VEGF in animal and human models of sepsis.2 The overexpression of sFlt-1 as well as the addition of exogenous sFLT-1 (each binds and neutralizes VEGF) in mice attenuated lipopolysaccharide- and CLP-mediated mediated morbidity (cardiac dysfunction, vascular permeability and endothelial activation) and mortality in sepsis. Importantly, these findings have been reproduced and extended by others.6 The striking and reproducible reduction in morbidity and mortality make a compelling case for further exploration in human sepsis.

A role for Bevacizumab in treating patients with severe sepsis. There are several advantages in employing Bevacizumab as a lead agent for inhibiting VEGF signaling in patients with severe sepsis. First, as a humanized monoclonal antibody, it has a sufficiently long half-life that it may be given as a single injection in this patient population. Second, it is already FDA approved for use in patients with certain types of cancer. Thus, there is extensive knowledge of its pharmacokinetics and pharmacodynamics (at least in the latter population). Moreover, it should not be difficult to obtain permission for use in septic patients. Third, its chief side effect, namely hypertension, will not be a major concern in sepsis, since this condition is associated with hypotension.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Medical Center
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper University Hospital
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Eligible patients are all adult patients, age > 18, who meet the following inclusion criteria:

  1. Evidence of infection a. temperature > 100.4F or < 97.0F of non-environmental causes, pneumonia as determined by the presence of an infiltrate on chest x-ray, a non-contaminated urinalysis with > 10 WBC or a urine dip-stick positive for leukocyte esterase, an abdominal CT scan yielding the diagnosis of an intra-abdominal etiology, skin/soft tissue infection on clinical exam.
  2. Two or more SIRS criteria a. tachycardia (HR>90) b. tachypnea (RR>20) or hypoxia (oxygen saturation<90%) c. hyperthermia >100.4 F (38C) or hypothermia <96F (35.5C) d. leukocytosis WBC> 15,000 cells/mm3 or bands>10%]
  3. Septic shock a. persistent hypotension (SBP < 90mmHg) after an initial 20-30 cc/kg fluid challenge, or the need for vasopressors for at least 1 hour in order to maintain a systolic blood pressure >90 mmHG; enrollment within 48 hours of meeting eligibility criteria.

Exclusion Criteria:

• Disease-Specific Exclusions:

  • Inability to obtain written informed consent from the patient or an appropriate designee General Medical Exclusions
  • Life expectancy of less than 12 weeks

• Bevacizumab-Specific Exclusions:

  • Inadequately controlled hypertension
  • Prior history of hypertensive crisis or hypertensive encephalopathy
  • New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E)
  • History of myocardial infarction or unstable angina within 12 months prior to Day 1
  • History of stroke or transient ischemic attack within 12 months prior to Day 1
  • Known CNS malignancy, except for treated brain metastasis
  • Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
  • History of hemoptysis within 1 month prior to Day 1
  • History of chronic bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study
  • Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
  • History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1
  • Serious, non-healing wound, active ulcer, or untreated bone fracture
  • Proteinuria at screening
  • Known hypersensitivity to any component of bevacizumab
  • Pregnancy or lactation
  • Any clotting abnormalities or a history of deep venous thrombosis or pulmonary embolus.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo IV for 90 minutes (+ 15 minutes)	Drug: Placebo; Placebo administered intravenously for 90 minutes (+ 15 minutes)
Experimental: Bevicizumab; IV infusion over 90 minutes	Drug: Bevacizumab; Administered intravenously 10 mg/kg over 90 minutes (+ 15 minutes); Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The change in Sequential Organ Failure Assessment score (SOFA) to assess reduction in organ failure	Between 0 and 72 hours

Secondary Outcome Measures

Outcome Measure	Time Frame
Mortality	In hospital
Inflammation signaling: the change in circulating levels of IL-6 and TNF-alpha level as the primary	1, 2, 3, 5, 7 and 28 days
Endothelial cell signaling/activation: change in E-selectin, ICAM-1, and sFLT	1, 2, 3, 5, 7, 28 days
VEGF signaling: measurement of VEGF levels in response to the study drug or placebo and determine if there is a reduction in overall VEGF signaling.	1, 2, 3, 5, 7, 28 days
Overall safety of Bevacizumab	Through Day 60

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: The Cooper Health System; Carolinas Medical Center
• Investigators: Principal Investigator: Nathan I Shapiro, MD, Beth Israel Medical Center

Publications and helpful links

General Publications

• Shapiro NI, Aird WC. Sepsis and the broken endothelium. Crit Care. 2011 Mar 21;15(2):135. doi: 10.1186/cc10044.

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Estimated): January 1, 2015
• Study Completion (Estimated): January 1, 2015

Study Registration Dates

• First Submitted: February 3, 2010
• First Submitted That Met QC Criteria: February 4, 2010
• First Posted (Estimated): February 5, 2010

Study Record Updates

• Last Update Posted (Actual): October 29, 2024
• Last Update Submitted That Met QC Criteria: October 27, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: septic shock; Bevacizumab; sepsis; Avastin
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Shock, Septic; Antineoplastic Agents, Immunological; Antineoplastic Agents; Physiological Effects of Drugs; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: 2009000036