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Safety of Darbepoetin Alfa Treatment in Patients With Severe Traumatic Brain Injury

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.
 
ClinicalTrials.gov Identifier: NCT00375869
Recruitment Status : Completed
First Posted : September 13, 2006
Last Update Posted : March 5, 2012
Sponsor:
Collaborator:
University of Alberta
Information provided by (Responsible Party):
Demetrios J. Kutsogiannis, Royal Alexandra Hospital

Tracking Information
First Submitted Date  ICMJE September 12, 2006
First Posted Date  ICMJE September 13, 2006
Last Update Posted Date March 5, 2012
Study Start Date  ICMJE November 2006
Actual Primary Completion Date December 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 23, 2011)
Neuron-specific serum enolase, CSF glutamate and CSF S100B levels in patients receiving darbepoetin compared to placebo [ Time Frame: over 96 hours ]
The primary outcome measures include Neuron-specific serum enolase, CSF glutamate and CSF S100B levels in patients receiving darbepoetin compared to placebo over a 96 hour period and ICP levels in patients receiving darbepoetin compared to placebo over a 96 hour period
Original Primary Outcome Measures  ICMJE
 (submitted: September 12, 2006)
The primary outcome measures include Neuron-specific serum enolase, CSF glutamate and CSF S100B levels in patients receiving darbepoetin compared to placebo over a 96 hour period and ICP levels in patients receiving darbepoetin compared to placebo over a
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2011)
Secondary outcome measures include ICU and hospital length of stay, GCS at ICU discharge, survival status, location after ICU and hospital discharge. GCS will be evaluated at day 28 and 1 year. [ Time Frame: day 28 and 1 year ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 12, 2006)
Secondary outcome measures include ICU and hospital length of stay, GCS at ICU discharge, survival status, location after ICU and hospital discharge. GCS will be evaluated at day 28 and 1 year.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety of Darbepoetin Alfa Treatment in Patients With Severe Traumatic Brain Injury
Official Title  ICMJE A Prospective Randomized Placebo Controlled Study of the Efficacy and Safety of Darbepoetin Alfa Treatment in Patients With Severe Traumatic Brain Injury
Brief Summary The purpose of this study is to see if the treatment of severely brain injured patients with darbepoetin (a long acting form of erythropoietin) will be safe, and will reduce brain damage by decreasing harmful levels of chemicals in the brain.
Detailed Description

Traumatic brain injury (TBI) is a common neurosurgical problem with a high morbidity and mortality. Studies interested in defining possible therapeutic targets in TBI have led to an appreciation of two phases of injury. These phases are referred to as primary and secondary TBI. The primary injury encompasses the immediate insult, diffuse axonal injury, hemorrhage, contusion, and primary ischemia. The secondary injury evolves over the post-traumatic period and is due to a combination of vasogenic and cytotoxic edema resulting from several processes including; glutamate excitotoxicity, disturbance of ionic homeostasis, lipid peroxidation, generation of nitric oxide (NO) and free radicals, and release of inflammatory regulators such as bradykinin and eicosanoids. It has long been recognized that one of the most important factors in the secondary injury process is the indiscriminate release of the excitatory neurotransmitter glutamate from neurons and glia. Glutamate excitotoxicity leads to substantial intraneuronal release of calcium which in turn mediates the activation of phospholipases which generate arachadonic acid, the activation of proteases, and the activation of NO, all of which cause neuronal membrane disruption and loss of ionic equilibrium. Receptors for erythropoietin (EPOr) are distributed throughout the brain and studies have demonstrated that these receptors are not only important in the process of development but also in neuroprotection. Treatment with erythropoietin (EPO) protects neurons in models of ischemic and traumatic degenerative damage due to exocitotoxins and consequent generation of free radicals including NO. EPOr activation also prevents the indiscriminate exocytosis of glutamate in a model of chemically induced ischemia on neurons of rat hippocampus.

The hypothesis of this study is that treatment of severely brain injured patients with darbepoetin alfa (Aranesp®) will be safe and reduce the cerebrospinal fluid (CSF) levels of glutamate within a 96 hour period after traumatic brain injury. This effect is potentially mediated through the activation of EPO receptors whose activation prevents the exocytosis of glutamate, a known neurocytotoxin, into CSF.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Traumatic Brain Injury
Intervention  ICMJE
  • Drug: Darbeopoetin
    The treatment group, comprised of ten patients, will receive an intravenous dose of 200 mcg (1 ml) of darbepoetin (Aranesp®). Patients will be randomly assigned to either the treatment group, or the control group in a 2:1 ratio. The treatment group will be given 200 mcg of darbepoetin intravenously. The control group will be given a matching placebo of 1 mL of normal saline.
    Other Name: ARANESP
  • Drug: Normal Saline (Placebo)
    The treatment group, comprised of ten patients, will receive an intravenous dose of 200 mcg (1 ml) of darbepoetin (Aranesp®). Patients will be randomly assigned to either the treatment group, or the control group in a 2:1 ratio. The treatment group will be given 200 mcg of darbepoetin intravenously. The control group will be given a matching placebo of 1 mL of normal saline.
    Other Name: Placebo
Study Arms  ICMJE
  • Active Comparator: Darbopoeitin
    The treatment group, comprised of ten patients, will receive an intravenous dose of 200 mcg (1 ml) of darbepoetin (Aranesp®). Patients will be randomly assigned to either the treatment group, or the control group in a 2:1 ratio. The treatment group will be given 200 mcg of darbepoetin intravenously. The control group will be given a matching placebo of 1 mL of normal saline.
    Intervention: Drug: Darbeopoetin
  • Placebo Comparator: Normal Saline (Placebo)
    The treatment group, comprised of ten patients, will receive an intravenous dose of 200 mcg (1 ml) of darbepoetin (Aranesp®). Patients will be randomly assigned to either the treatment group, or the control group in a 2:1 ratio. The treatment group will be given 200 mcg of darbepoetin intravenously. The control group will be given a matching placebo of 1 mL of normal saline.
    Intervention: Drug: Normal Saline (Placebo)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 23, 2011)
10
Original Enrollment  ICMJE
 (submitted: September 12, 2006)
15
Actual Study Completion Date  ICMJE December 2009
Actual Primary Completion Date December 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 18-70 inclusive.
  • Admitted to ICU with a TBI and a GCS ≤ 8 with a motor score < 6.
  • Patient must have a functioning external ventricular drain in place for intracranial pressure (ICP) monitoring.
  • Completion of informed consent by the next-of-kin or legal guardian.
  • Randomization within 12 hours of initial triage by medical or paramedical staff.
  • Abnormal CT of the brain.

Exclusion Criteria:

  • Pregnancy
  • Cardiac arrest during the current hospital admission.
  • Bilateral non-reactive dilated pupils at the time of randomization.
  • A history of renal failure, NYHA class IV congestive heart failure, or recent myocardial infarction (within 6 months).
  • A history of primary or secondary polycythemia.
  • Previous adverse reactions to rhEPO or darbepoetin.
  • Previous history of seizure disorder.
  • Recent history (within the past 3 months) of significant uncontrolled hypertension defined as SBP > 200 mm Hg or DBP > 110 mmHg.
  • Patients involved in other clinical investigations involving therapeutic interventions
  • Hemoglobin ≥150 g/L in females
  • Hemoglobin ≥160g/L in males
  • Past history of thrombotic events
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00375869
Other Study ID Numbers  ICMJE TBI2006
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Demetrios J. Kutsogiannis, Royal Alexandra Hospital
Study Sponsor  ICMJE Royal Alexandra Hospital
Collaborators  ICMJE University of Alberta
Investigators  ICMJE
Principal Investigator: Demetrios J. Kutsogiannis, MD MHS FRCPC Division of Critical Care Medicine
PRS Account Royal Alexandra Hospital
Verification Date March 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP