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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2010 by Beth Israel Deaconess Medical Center.
Recruitment status was  Not yet recruiting
Sponsor:
Collaborators:
The Cooper Health System
Carolinas Medical Center
Information provided by:
Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier:
NCT01063010
First received: February 3, 2010
Last updated: February 4, 2010
Last verified: February 2010
  Purpose

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 Intervention
Septic Shock
Drug: Bevacizumab
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pilot Study of Bevacizumab (Avastin) in Patients With Septic Shock

Resource links provided by NLM:


Further study details as provided by Beth Israel Deaconess Medical Center:

Primary Outcome Measures:
  • The change in Sequential Organ Failure Assessment score (SOFA) to assess reduction in organ failure [ Time Frame: Between 0 and 72 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • Endothelial cell signaling/activation: change in E-selectin, ICAM-1, and sFLT [ Time Frame: 1, 2, 3, 5, 7, 28 days ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Overall safety of Bevacizumab [ Time Frame: Through Day 60 ] [ Designated as safety issue: Yes ]
  • Mortality [ Time Frame: In hospital ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: February 2010
Estimated Study Completion Date: January 2011
Estimated Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01063010

Contacts
Contact: Daniel Johnston, BSN (617) 754-2232 dsjohnst@bidmc.harvard.edu

Locations
United States, Massachusetts
Beth Israel Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Daniel Johnston, BSN    617-754-2332    dsjohnst@bidmc.harvard.edu   
Principal Investigator: Nathan I Shapiro, MD         
United States, New Jersey
Cooper University Hospital Not yet recruiting
Camden, New Jersey, United States, 08103
United States, North Carolina
Carolinas Medical Center Not yet recruiting
Charlotte, North Carolina, United States, 28203
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
The Cooper Health System
Carolinas Medical Center
Investigators
Principal Investigator: Nathan I Shapiro, MD Beth Israel Medical Center
  More Information

No publications provided by Beth Israel Deaconess Medical Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Nathan I. Shapiro, MD, MPH, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT01063010     History of Changes
Other Study ID Numbers: 2009-000036
Study First Received: February 3, 2010
Last Updated: February 4, 2010
Health Authority: United States: Food and Drug Administration

Keywords provided by Beth Israel Deaconess Medical Center:
sepsis
septic shock
Bevacizumab
Avastin

Additional relevant MeSH terms:
Shock, Septic
Shock
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 16, 2014