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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01063010
Recruitment Status : Withdrawn (no participants enrolled)
First Posted : February 5, 2010
Last Update Posted : March 16, 2017
The Cooper Health System
Carolinas Medical Center
Information provided by (Responsible Party):
Nathan Shapiro, Beth Israel Deaconess Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Septic Shock Drug: Bevacizumab Drug: Placebo Not Applicable

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  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pilot Study of Bevacizumab (Avastin) in Patients With Septic Shock
Study Start Date : February 2010
Estimated Primary Completion Date : January 2015
Estimated Study Completion Date : January 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Shock
Drug Information available for: Bevacizumab

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 Name: Avastin

Primary Outcome Measures :
  1. The change in Sequential Organ Failure Assessment score (SOFA) to assess reduction in organ failure [ Time Frame: Between 0 and 72 hours ]

Secondary Outcome Measures :
  1. Inflammation signaling: the change in circulating levels of IL-6 and TNF-alpha level as the primary [ Time Frame: 1, 2, 3, 5, 7 and 28 days ]
  2. Endothelial cell signaling/activation: change in E-selectin, ICAM-1, and sFLT [ Time Frame: 1, 2, 3, 5, 7, 28 days ]
  3. 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. [ Time Frame: 1, 2, 3, 5, 7, 28 days ]
  4. Overall safety of Bevacizumab [ Time Frame: Through Day 60 ]
  5. Mortality [ Time Frame: In hospital ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01063010

United States, Massachusetts
Beth Israel Medical Center
Boston, Massachusetts, United States, 02215
United States, New Jersey
Cooper University Hospital
Camden, New Jersey, United States, 08103
United States, North Carolina
Carolinas Medical Center
Charlotte, North Carolina, United States, 28203
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
The Cooper Health System
Carolinas Medical Center
Principal Investigator: Nathan I Shapiro, MD Beth Israel Medical Center

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Nathan Shapiro, Associate Professor of Emergency Medicine, Beth Israel Deaconess Medical Center Identifier: NCT01063010     History of Changes
Other Study ID Numbers: 2009000036
First Posted: February 5, 2010    Key Record Dates
Last Update Posted: March 16, 2017
Last Verified: March 2017

Keywords provided by Nathan Shapiro, Beth Israel Deaconess Medical Center:
septic shock

Additional relevant MeSH terms:
Shock, Septic
Pathologic Processes
Systemic Inflammatory Response Syndrome
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents